Personal Use Only Not for Distribution

0 downloads 0 Views 2MB Size Report
Arvinte, T.; Merkle, H.P. Architecture and polymorphism of fibrillar supramolecular ..... interaction partners tell many different stories. Trends Biochem. .... [108] Will, R.G.; Ironside, J.W.; Zeidler, M.; Cousens, S.N.; Estibeiro,. K.; Alperovitch, A.

Send Orders for Reprints to [email protected] Current Protein and Peptide Science, 2018, 19, 858-875

REVIEW ARTICLE ISSN: 1389-2037 eISSN: 1875-5550

Emerging Targets and Latest Proteomics Based Therapeutic Approaches in Neurodegenerative Diseases

Impact Factor: 2.696


Munazza Tamkeen Fatima1, Zeyaul Islam2, Ejaj Ahmad3 and Parveen Salahuddin4,* 1

Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas (UNICAMP), Campinas, SP, 13083-862, Brazil; 2Laboratório Nacional de Biociências, Centro Nacional de Pesquisa em Energia e Materiais, Campinas, SP, 13083-100, Brazil; 3School of Pharmacy, Fudan University, Key Laboratory of Smart, Drug Delivery of MOE and PLA, Shanghai 201203, China; 4DISC, Interdisciplinary Biotechnology Unit, A.M.U., Aligarh, 202002, India

ARTICLE HISTORY Received: December 05, 2017 Revised: February 28, 2018 Accepted: March 15, 2018

Pe N rs ot on fo al rD U is se tri O bu n tio ly n

Current Protein & Peptide Science


DOI: 10.2174/1389203718666170731114757

Abstract: Protein homeostasis (proteostasis) is achieved by the interplay among various components and pathways inside a cell. Dysfunction in proteostasis leads to protein misfolding and aggregation which is ubiquitously associated with many neurodegenerative disorders, although the exact role of these aggregate in the pathogenesis remains unknown. Many neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and others are characterized by the conversion of specific protein aggregates into protein inclusions and/or plaques in degenerating brains. Apart from the conventional disease specific proteins, such as amyloid-β, α synuclein, huntingtin protein, and prions that are known to aggregate, a number of other proteins play a vital role in aggravating the disease condition. In this review, we discuss the disease etiology, mechanism, the role of various pathways, molecular machinery including molecular chaperones, protein degradation pathways, and the active formation of inclusions in various neurodegenerative diseases. We also highlight the approaches, strategies, and methods that have been used for the treatment of these complex diseases over the years and the efforts that have potential in the near future.

Keywords: Protein misfolding, aggregation, chaperones, proteosomes, small molecule inhibitors. 1. INTRODUCTION

Proteins are synthesized on ribosomes as a linear polypeptide chain and are involved in almost every biological process due to their versatility and structural complexity. The folding of these polypeptide chains into the native state is a basic prerequisite for its biological activity. Protein folding is a thermodynamically driven process where the hydrophobic amino acids form the core of the protein, while hydrophilic amino acids reside at the surface making favorable interaction with the aqueous environment. As a consequence an expanded protein chain collapses rapidly to a globular structure, reshuffles within and finally gives rise to the native three dimensional structures that correspond to the most stable, biologically active state [1]. Folding of a protein in vitro differs in many details from that in the cell. However, one feature which is common in both in vitro and inside the cell is the presence of the intermediate state of the foldingunfolding pathway [2, 3]. The folding of a protein becomes more challenging in vivo owing to the shear cellular crowding (cytosolic protein concentration ~300-400 g/l). Crowding *Address correspondence to this author at the DISC, Interdisciplinary Biotechnology Unit, A.M.U., Aligarh, 202002, India; Tel: +91-571-2720388; Fax: +91-571- 2721776; E-mail: [email protected]

1875-5550/18 $58.00+.00

may possibly assist the functional interactions among macromolecules, but it also increases the chance of partially folded, non-native and structurally flexible proteins to aggregate [4]. Some naturally occurring proteins seem to be inherently devoid of any ordered structure and adopt folded conformations only after interaction with their binding partners [5]. These metastable proteins, such as tau and α synuclein, have a tendency to form fibrillar aggregates that are associated with dementia and Parkinson’s disease. Thus, protein quality control and the maintenance of proteome homeostasis (known as proteostasis) are crucial for cellular functionality. Proteostasis can be accomplished by a cooperative network of various proteins [6], most prominent being the molecular chaperones and their regulators, followed by the ubiquitin proteasome system (UPS) and autophagy system, which degrade and clear out the highly misfolded and aggregated proteins (Fig. 1). Imbalance in proteostasis leads to numerous diseases, such as neurodegeneration and dementia, type 2 diabetes, peripheral amyloidosis, lysosomal storage disease, cystic fibrosis, cancer and cardiovascular disease. Molecular chaperones are highly specialized and conserved groups of proteins which protect the protein from misfolding and aggregation in the exceedingly crowded cellular milieu, and allow them to fold efficiently and on a cel-

© 2018 Bentham Science Publishers

Emerging Targets and Latest Proteomics Based Therapeutic

Current Protein and Peptide Science, 2018, Vol. 19, No. 9

Unfolded proteins


Degradation (Proteolysis)

Chaperone Misfolded proteins/ Partiallyfolded intermediates

Native proteins

Protein aggregates

Autophagy Ubiquitin Autophagosome Lysosome

Proteasome degradation

Pe N rs ot on fo al rD U is se tri O bu n tio ly n




Fig. (1). A simplified illustration of protein quality control inside the cell. Coordinate action of molecular machinery to maintain the protein homeostasis. Chaperones help in folding the nascent polypeptides coming out from the ribosome, although some small domain proteins fold spontaneously without the help of chaperones. It also help in unfolding the misfolded proteins, and their degradation by the ubiquitin– proteasome system (UPS). Misfolded proteins may evade the targeted degradation, which leads to the formation of aggregates via hydrophobic interactions. Aggregated proteins can be clear out by the autophagy-lysosome. Altercation in these machinery leads to various neurodegenerative pathologies.

lular relevant timescale [7]. However, malfunctioning of these chaperones or change in the environmental conditions are associated with the misfolding and aggregation of the newly synthesized protein adding to a good number of neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's chorea (HC), Amyotrophic lateral schlerosis (ALS) and prion diseases (Creutzfeldt–Jakob disease, CJD), kuru, fatal familial insomnia and Poly glutamate diseases. These aggregates are usually fibrils of β-amyloid (Aβ) and tau proteins in AD, α synuclein in PD, Huntingtin in HD, and mutant SOD1 protein in ALS disease. In fact, each neurodegenerative disease mentioned above is associated with one or more amyloid proteins (AP) and the presence of these proteins in a specific functional-anatomical region is manifested as disease conditions [8]. The core structure of Aβ, α-synuclein and poly-glutamine aggregates mainly includes β-sheet which is comprehended to be common to neurodegerative related amyloids. Also, in the case of CJD, the α-helices of the wild type protein, PrPC are converted into β-sheet dominant PrPSc, thereby causing misfolding and aggregation. The harmful effects of the misfolded proteins in the above cases are due to the deposition of these aggregates in the brain leading to cytotoxicity and ultimately death of the neurons. Misfolding, however, may also lead to a loss of function as in the case of cystic fibrosis (CF) and α1-antitrypsin deficiency. In addition, protein misfolding is also responsible for many p53mediated cancers. Rational therapeutic approaches to prevent protein aggregates or removal/solubilization of the already formed aggregates are an exceedingly challenging in the present scenario, with the disease hitting millions of people

around the globe. Molecular chaperones form the first line of defense, most of which are stress inducible like the heat shock proteins (Hsps) including Hsp 100, Hsp 90, Hsp 70, Hsp 60 and other small Hsps. The Hsp100 has disaggregation activity and Hsp104 along with Hsp 70 has solubilization potential, suggesting their diverse functionality. Activating the cellular chaperone is one of the efficient way of increasing the folding potential, degradation of proteins with destabilizing mutations is another way to achieve the desired result [9]. For instance, it has been proposed that small molecules like geldanamycin trigger heat shock factor 1, which effectively increases the cytosolic chaperone concentrations, which thereby help in suppressing the aggregation as well as correcting the misfolding of various disease proteins [9-13]. This approach of overexpression of chaperones such as Hsp70 and Hsp40 has been shown to be effective and numerous evidence is present, suggesting that the overexpression prevents aggregation and toxicity of Huntingtin and α-synuclein diseases [10, 14-18]. Numerous small molecule inhibitors are therefore being developed to inhibit aggregation process. RNA interference and active and passive immunization are among other alternative approaches. With varying clinical symptoms, most of the neurodegerative diseases are associated with the abnormal loss of neurons. They share common pathogenic mechanisms involving misfolding and aggregation and these aggregates are deposited in the central nervous system (CNS). Amyloid formation is the result of partial unfolding of misfolded protein leading to the exposure of hydrophobic surfaces that interact with similar structure and gives rise to an oligomer

860 Current Protein and Peptide Science, 2018, Vol. 19, No. 9

generally recognized to the longer life span of women relative to men [32]. The third factor is ApoE4 allele [33-35] and among persons diagnosed with AD, up to 60% carry at least one ε4 allele [36]. Apolipoprotein E (ApoE) is a 34-kDa lipid binding protein that functions in the transport of triglycerides and cholesterol in multiple tissues, including the brain and interacts with lipoprotein receptors [37, 38]. It is considered as an amyloid-β (Aβ) chaperone due to the presence of Aβ-binding motif [38] and this interaction can activate intracellular Aβ degradation by guiding the amyloid to lysosomes. The complexity of the interplay between this triad of risk factors (age, sex, and apolipoprotein E) along with associated factors leads to late onset Alzheimer’s disease (LOAD). The mechanism involved in AD is cleavage of a 42 amino acid peptide, β amyloid from the amyloid precursor protein (APP) which is a long chain trans-membrane protein. The whole process involves the enzyme β-secretase, which is a beta-site APP-cleaving enzyme (BACE) that cleaves the APP to form a β amyloid precursor peptide Aβ, and this is further cleaved by another aspartyl protease, γ -secretase to produce Aβ-42 (amyloidogenic form) instead of the normal Aβ-40 [8, 39]. This peptide, which normally undergoes cellular degradation, forms extracellular aggregates owing to the formation of the beta pleated sheet with extensive interchain H-bonding and consequently generates amyloid plaques in some patients [40]. Most of the cases of AD are sporadic, but genetic factors have also been reported in which mutations in the gene encoding the amyloidgenic protein occurs, making it more prone to misfolding and aggregation [41]. Precisely, autosomal dominant mutations in APP, PS1 or PS2 genes describe the familial early-onset AD and account for 3–5% of the total AD cases. These mutations result in an increase in amyloid peptide production and plaque formation [42, 43]. The acquired and genetic forms have different timings of expression/manifestation of the disease with the acquired forms being expressed late and slowly, and the genetic forms onsetting early and progressing fast [44]. Approximately 95% of the cases of AD are sporadic [43]. The acquired forms of AD may also occur due to the loss of the ubiquitin proteosome system (UPS) [45] or because of the high intrinsic disposition of some proteins to escape all protective mechanisms and thereby undergo misfolding and aggregation [46]. Dimerization and oligomerization forms of the Aβ fragments have been reported to increase the neurotoxicity [47]. Studies have shown that the internal hydrophobic region flanked by amino acids 17 (Leucine) and 21 (Alanine) is critical for the early steps of Aβ misfolding and aggregation, indicating that hydrophobic interactions drive the Aβ assembly [48, 49]. This is consistent with the higher propensity of Aβ peptides to aggregate due to the presence of two or three extra hydrophobic amino acids at the carboxyl terminus [50]. In general, the location of amino acid substitutions within regions of the sequences plays a vital role in the aggregation process. For example, mutations that decrease the hydrophobicity of the nucleation site can decrease the aggregation propensity or vice-versa [51-53]. Secondly, the charge is also speculated to form an important factor in protein aggregation. This is because in the presence of a high net positive charge proteins experi-

Pe N rs ot on fo al rD U is se tri O bu n tio ly n

and eventually fibrillar structure. The structure of fibrils, when visualized by transmission electron microscopy (TEM) or atomic force microscopy (AFM), appears to consist of a number of (2-6) protofilaments where each protofilament is about 2-5 nm in diameter, which is often twisted around each other, to form supercoiled rope like structures, that is 7-13 nm wide [19, 20]. The protofilaments may also associate laterally to form long ribbons of 2-5 nm thick and up to 30 nm wide [21, 22]. Structural characterization by circular dichroism, Fourier transform infra-red spectroscopy, solidstate NMR (nuclear magnetic resonance) [23] and X-ray fiber diffraction data have shown that each protofilament is arranged such that β -strands stack in the register and run perpendicular to the long axis of the fibril and generate a structure known as cross-β structure [19]. Each strand in β sheets is arranged in such a way with the neighboring strand that favors the formation of hydrogen bonds with the strands above and below the fibril. Apart from the usual arrangement, recent data have shown that in some cases an antiparallel pair of the strand is not synced with neighboring pairs by six residues, leaving hydrogen bonds dangling [24]. These out-of-register β-sheets (amyloid fibril) assume cylindrins structure which may be cytotoxic in nature [24]. These fibrillar aggregates are known to bind dyes (Congo red and thioflavin T) that intercalate into the β sheet of the amyloids [25] implying the presence of higher order structure. Interestingly, these fibrillar aggregates accumulate in the early stages in the patient’s life but are expressed later in the form of disease symptoms. The observed phenotypic multiplicity in the different forms of amyloidosis is largely attributed to the heterogeneities and insolubilities of oligomeric and fibrillar structures as well as the differences in the protein constituents [26]. Further, it has been found that different individual acquires the aggregates at a different time of their life and also in different regions of the brain [27].

Fatima et al.

In this review, we have focused on the molecular mechanisms underlying these neurodegenerative diseases. We have also extensively discussed all possible therapeutic strategies that could combat and potentially reduce the high morbidity and mortality rates associated with these neurodegenerative diseases, especially in the developed nations. 1.1. Alzheimer’s Disease

Alzheimer’s disease (AD) is characterized by the degeneration of pyramidal neurons in the basal forebrain and hippocampus. This eventually leads to the development of late onset dementia, loss of working ability, speech, and recognition [28]. More than 35 million people worldwide are affected by the disease and this number is growing rapidly due to the increase in the elder people in the overall human population [29]. The financial and social cost is also increasing and with existing AD treatments, the trends are not looking good and the need for therapeutics is becoming urgent.

There are three major risk factors associated with AD. First one is age, the fundamental driver for the development of disease [29, 30]. Between 2015 and 2030, the number of people in the world aged 60 years or over is projected to grow by 56% and by 2050 the globally aged population is projected to more than double [31]. The second factor is female sex, where the prevalence of AD is well known and is

Emerging Targets and Latest Proteomics Based Therapeutic

ence electrostatic repulsion leading to partial unfolding and consequently the protein undergoes aggregation [54, 55].


ronal loss. By the time of death, the brain loses 50–70% of its neurons as compared with the healthy individuals [69]. PD is also characterized by the depletion of dopamine in the caudate nucleus and nucleus accumbens [71]. PD is usually sporadic, but single gene mutations in the genes encoding α -synuclein (SNCA) and other genes including ubiquitin C-terminal hydrolase like 1(UCH-L1), parkin (PRKN), LRRK 2, PINK 1 and DJ-1 have been identified [69, 72, 73]. With the notable exception of LRRK 2, these single gene defects account only a small number of patients with PD [74]. Interestingly, in juvenile cases, mutations in the parkin protein results in parkinsonian syndrome (without Lewy bodies), suggestive of the major role of parkin protein in the growth of the Lewy bodies [69]. Further, it has been found that parkin facilitates ubiquitination of proteins such as synphilin-1 (α-synuclein interacting protein) leading to the formation of Lewy bodies [75]. The LRRK 2 gene (PARK8) has been reported to be the most common cause of familial or sporadic PD. The frequency of LRRK2 mutations in patients with a family history of PD is 5–7% [74]. Many of the LRRK2 patients reported having typical features of PD with onset in middle or late.

Pe N rs ot on fo al rD U is se tri O bu n tio ly n

In addition to the extracellular plaques containing Aβ peptides, lesions observed in AD are also characterized by intracellular neurofibrillary tangles (NFTs) that contain insoluble proteinaceous deposits of hyper-phosphorylated tau proteins [56]. Under normal conditions, tau stabilizes the microtubules (MTs), essential for the axonal transport of proteins and other cellular components [57]. Tau malfunctions can thus lead to destabilization of microtubules leading to synaptic dysfunction and neuronal loss hence causing axonal transport deficits [54]. NMDARs (N-methyl-Daspartate receptors) has been recently implicated in AD because activation of these receptors is related to the changes caused due to AD characteristics like synaptic loss, deposition of Aβ plaques, NFTs, and hyper-phosphorylated tau. Aβ has also been shown to trigger NMDA-mediated Ca2+influx, excitotoxicity, and stress-related signaling pathways in neurons which may cause age-related increases in oxidative stress, impaired energy metabolism, and defective Ca2+ homeostasis [38, 57] suggesting both proper synapse function and NMDAR are necessary for learning and memory.

Current Protein and Peptide Science, 2018, Vol. 19, No. 9

Recent epidemiological, clinical, and animal studies suggest that diabetes significantly increases the risk of developing AD and a possible mechanistic relationship underlies these two important clinical disorders [58, 59]. It has been analyzed that there is significantly reduced levels of insulin, insulin-like growth factor 1 (IGF-1) and its receptors in advanced AD brain compared to aged control brains [60]. The correlation is also supported by the observation that patients with AD are more vulnerable to diabetes and glucose intolerance [61, 62]. Aβ and phosphorylated tau accumulation occurs in both type 1 and type 2 diabetes and it appears to be associated with insulin resistance and possibly hypercholesterolemia [63]. Insulin dysfunction induced abnormal tau hyper-phosphorylation through two distinct mechanisms, one is through hypothermia and the other is probably caused by inhibition of phosphatase activity [64]. Although type 1 and type 2 diabetes may contribute to AD through different mechanisms, whereas insulin deficiency may be the major contributing factor in type 1 diabetes, in type 2 diabetes, hyperglycemia-mediated tau cleavage may be the key feature [65]. Due to these associations between AD and diabetes, in recent years, AD is even referred to as type 3 diabetes [62]. An understanding of the relationship between diabetes and AD might offer novel approaches to modulating the onset and progression of either disorder. 1.2. Parkinson’s Disease

Parkinson’s disease (PD) is the second most prevalent chronic progressive neurodegenerative disorder among the elderly after Alzheimer’s disease [66]. In PD, the clinical symptoms include bradykinesia, muscular rigidity, and postural instability. Tremor, combined with slowness and stiffness in the arm are often observed in PD [67]. PD is characterized by the presence of aggregates called Lewy bodies in the cytoplasm of neurons from the substantia nigra that particularly affect the ventral component of the pars compacta [68, 69]. The major constituents of these aggregates are fragments of the protein, α -synuclein [70], that lead to neu-

Substantial research into mitochondrial genetics and its role in PD has been detailed recently. For instance, mutations in Complex 1 of the oxidative phosphorylation pathway have been detected in PD brains, blood platelets and skeletal muscle [76, 77]. Thus, it is concluded that the cells of the pars compacta are particularly susceptible to oxidative damage [78]. Environmental factors are also known to be vital in synucleinopathies, for example, environmental toxins such as pesticides and wood preservatives are known to affect PD [79]. Use of pesticides paraquat and maneb, for example, has been reported to involve the nociceptin/orphanin-NOP and prodynorphin-KOP systems in a chronic paraquat and maneb animal model of Parkinson's disease. Results indicate a significant reduction in tyrosine hydroxylase (TH) levels, the rate-limiting enzyme for dopamine synthesis. The paraquat and maneb induced an increase in nociceptin/orphanin and a decrease of prodynorphin gene expression levels in the substantia nigra with a down-regulation of NOP and KOP receptors after treatments in the substantia nigra and caudate putamen. These data further confirm that paraquat and maneb toxicity can modulate gene expression of the nociceptin/orphanin-NOP receptor and prodynorphin-KOP receptor systems in the substantia nigra and caudate putamen, offering further support to the hypothesis that chronic exposure to these hazardous environmental toxins led to sporadic Parkinson's disease [80]. Mitochondrial dysfunction in PD may be triggered by one or more environmental toxins [69]. α-synuclein has also been proposed to have substantial long-range interactions between the negatively charged Cterminal and the central amyloidogenic NAC (Non Abeta Component) region [81]. Structural perturbations with positively charged ions, which interact with the negatively charged C terminus, thereby neutralize the charge. Similarly, a decrease in the pH reduces the net charge of the C-terminal region, and deletion of the C terminus reduces the net charge of the protein. All of these factors led to prompt aggregation

862 Current Protein and Peptide Science, 2018, Vol. 19, No. 9

Fatima et al.

[82]. Additionally, failure of the UPS resulted in the abnormal aggregation of proteins including α-synuclein [83]. 1.3. Huntington’s Disease Huntington disease (HD) is a rare, autosomal-dominant progressive neurodegenerative disorder of the CNS, characterized by unwanted choreatic movements, cognitive decline, behavioral and psychiatric disturbances and dementia [84]. The disease onset generally is in adulthood between 30 and 50 years, although manifestation of the disorder can occur any time between infancy and senescence [85].

Thus, the chaperones either promote refolding of misfolded proteins or participate in their ubiquitination (Ub), thereby degrading them by 26S proteasome machinery, or else the misfolded htt protein accumulates in the cytoplasm. Proteolytic cleavage of mutant htt may yield fragments that can form β -sheet structures which are either translocated to the nucleus and block transcription by forming soluble or insoluble aggregates or tend to damage to normal vesicle transport, clathrin-mediated endocytosis, and mitochondrial protein functions in the cytoplasm.

Pe N rs ot on fo al rD U is se tri O bu n tio ly n

Huntingtin (htt) protein is the key protein involved in the HD pathology (Fig. 2). This protein has been reported to play an important role in vesicular transport, cytoskeletal anchoring, clathrin-mediated endocytosis, neuronal transport and postsynaptic signaling [86, 87]. It forms part of the dynactin complex, localizes with microtubules and interacts with β -tubulin. Furthermore, htt can protect neuronal cells from apoptotic stress [88]. HD is caused by an elongated CAG repeat (36 repeats or more) on the short arm of chromosome 4p16.3 in the Huntingtin gene [89] leading to a polyglutamine strand of variable length at the N-terminus. Evidence suggests that this tail confers a toxic gain of function. The longer the CAG repeat, the earlier the onset of disease. In cases of juvenile HD, the repeat often exceeds 55. The longer the poly Q domain, the greater is the charge-charge repulsion in this domain leading to the unfolding of Nterminus in the huntingtin protein. This promotes the formation of intracellular aggregates as nuclear inclusions [90]. Extracellular aggregates have also been reported [91]. Htt, along with other polyQ proteins interact with the Hsp70 and Hsp40 family of chaperones, and they also colocalize with these aggregates [92]. The confiscation of chaperones into aggregates decreases the amount of soluble chaperones pre-

sent inside the cell [93]. Normally, if chaperones are unable to refold abnormal proteins correctly, then they promote their ubiquitination, which ultimately directs them to the proteasome for degradation. Inclusion bodies formation in HD together with their association with several proteasome subunits, strongly suggest a failure in the degradative machinery of the cell and hence the manifestation of the diseased condition. Other polyQ related disorders (tandem polyglutamine repeats) are spinal bulbar muscular atrophy (SBMA), dentatorubropallidoluysian atrophy (DRPLA), and six types of spinocerebellar ataxia (SCA1, 2, 3, 6, 7, and 17) [94].

1.4. Amyotrophic Lateral Sclerosis ALS is characterized by progressive paralysis of the limb muscles, speech, swallowing, and respiration due to the progressive degeneration of voluntary motor neurons [95]. In addition to its sporadic occurrence, it is caused by a missense mutation in a Cu/Zn-superoxide dismutase (SOD1) gene [96], TAR-DNA binding protein 43 (TDP43) [97], or RNAprocessing proteins fused in sarcoma/translocated in liposarcoma (FUS/TLS) [98]. Superoxide dismutases are enzymes that alternately catalyze the dismutation (or partitioning) of the superoxide (O2-) radical into molecular oxygen or H2O2.

Impaired folding

Proteasome degradation

Chaperone assisted folding

Native htt


Misfolded htt

polyQ-- Translated htt

Chaperone refolding

Intranuclear inclusions

Nuclear sequestration and aggregation

Impaired transcription

Proteasome dysfunction

Nuclear translocation

Cytoplasmic sequestration and aggregation

Clathrin mediated endocytosis dysfunction Mitochondrial toxicity Vesicle transport dysfunction Fig. (2). Cellular pathogenesis in Huntington’s disease (HD). The HD mutation induces conformational changes and is likely to cause the abnormal folding of htt, which, if not corrected by chaperones, leads to the accumulation of misfolded htt in the cytoplasm. Toxicity might be elicited by mutant full-length htt or by cleaved N-terminal fragments, which may form soluble monomers, oligomers or large insoluble aggregates. In the cytoplasm, mutant forms of htt may impair the ubiquitin–proteasome system (UPS), leading to the accumulation of more proteins that are misfolded In addition, mutant htt can be translocated into the nucleus to form nuclear inclusions, which may disrupt transcription.

Emerging Targets and Latest Proteomics Based Therapeutic

They are ubiquitously-expressed and are essential for maintaining antioxidant homeostatic control in vivo. They are associated with the misfolding of the normally stable homodimeric protein _ENREF_7 [99]. Contrary to this, studies indicate that misfolded SOD1 occurs in sporadic forms of ALS in which SOD1 mutation is excluded [100]. FUS/TLS and TDP43 are predominantly nuclear proteins that participate in common heteromultimeric complexes [101], RNA transcription, translation, splicing, nucleocytoplasmic shuttling and stress granule formation [102]. Under pathological conditions, FUS/TLS and TDP43 are redistributed to the cytosol and participate in abnormal protein-protein association [103], leading to the formation of cytoplasmic aggregates and manifestation of ALS diseases [104]. TDP43 has also been reported to amass in the neuronal cytosol in other neurodegenerative diseases (e.g., Alzheimer’s disease). Hence, it is a marker of these diseases [102].


from its primarily soluble α-helical structure to an insoluble β sheet conformation, instigated by direct interaction with PrPRES, a misfolded and protease-resistant form of the cellular prion protein (PrPC) present in the infectious agent. PrP misfolding replicates in a cyclic manner, with the newly generated PrPRES catalyzing the generation of more pathological prions at the cost of endogenous PrPC [110, 111]. Thus, the misfolded prion protein is believed to replicate in the brain independent of nucleic acids. PrP is encoded by a single exon as a polypeptide chain of 250 to 260 amino acids depending on the species [112]. In humans, PrPc is synthesized as a 254 amino acid precursor. The nascent peptide is cleaved at both the N- and C-terminal in the ER and a glycosylphosphatidylinositol (GPI) anchor is attached to it at position 231. In the Golgi, PrPc is Nglycoslyated at positions 181 and 197 [113, 114]. Mature PrPc consists of the amino acid residues 23-231 and is expressed as a membrane glycoprotein anchored to the cell surface by a GPI moiety. Thus, after an extensive posttranslational processing in the ER and Golgi complex and trafficking through the secretory pathway, fully matured PrPc localizes to cholesterol-rich lipid rafts, and cycles through the endocytic pathway [115]. During the folding at the ER, approximately 10% of PrPc is naturally misfolded and eliminated by the proteasome through the ER-associated degradation (ERAD) pathway [116]. The rate of ERAD-mediated degradation is substantially increased for familial PrP mutant forms [117]. Most familial mutant PrP variants are retained and aggregated in the ER and Golgi, where they may exert their pathological effects [118].

Pe N rs ot on fo al rD U is se tri O bu n tio ly n

1.5. Prion Diseases /Transmissible Spongiform Encephalopathy

Current Protein and Peptide Science, 2018, Vol. 19, No. 9

These are a family of fatal neurodegenerative diseases affecting a number of mammalian species. TSE was first discovered in sheep as scrapie. In cattle, they occur as bovine spongiform encephalopathy (BSE) or mad cow disease and in cervids as chronic wasting disease (CWD). The five subtypes constituting the human prion diseases are kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-StrausslerScheinker syndrome (GSS), fatal insomnia (FI), and variant CJD (vCJD). These subtypes are distinguished primarily by observing the differences in the pathogenic conformation of misfolded protein PrP in the brain by histopathology and clinical phenotype analysis. TSEs in humans can be divided into sporadic, familial, and infectious groups. The majority of the cases are sporadic, with the worldwide incidence being roughly one per million populations per year [105]. Nearly 10 to15 percent of this manifestation results from an autosomal dominant mutation of the PrP gene (PRNP), all associated with familial TSEs including some forms of CJD, GSS syndrome and FFI [106]. Infectious TSE diseases including kuru propagate by ritualistic cannibalism, and iatrogenic CJD, which is spread by tissue transplantation, contamination of surgical tools or inoculation with materials derived from CJD-infected tissues [107]. New variant CJD (vCJD) is a novel infectious disease which was first described in 1996 [108]. Primary symptoms include progressive dementia and ataxia. Amyloid fibrils accumulate within the cells creating vacuous spaces in the neuropil (spongiform degeneration), the pathologic hallmark of the terminal phase of all prion diseases [109].

Misfolding and consequent aggregation of an abnormal prion protein are the principal mechanisms of TSE diseases. The normal prion protein (PrPc) is protease sensitive, soluble, and has a high α -helical content, although its normal function is not yet known. The disease-causing prion protein (PrPsc/ PrPRES, the transmissible isoform) is protease resistant and insoluble and forms amyloid fibrils that have high β sheet content. According to the protein-only hypothesis, these prion aggregates are proposed to expand autocatalytically, by forming protein oligomers which act as a template to promote protein misfolding and aggregation. Briefly, a conformational change occurs in the natively folded PrPc

The three dimensional structure of the PrP reveals the presence of two short anti-parallel β -sheets (S1 and S2), a small α-helix (H1) and two anti-parallel helices (H2 and H3) linked by the single disulfide bond. H2 and H3 remain stabilized via the disulfide bond [119, 120]. PrPc is composed of 42% α -helix and 3% β -sheet while PrPsc contains 30% αhelix and 43% β-sheet. The β-sheet-rich conformation has a high propensity to recruit additional β -sheet monomers to form the irreversible, disease-related isoform. Thus, the two β-strands S1 and S2 are proposed to “seed” β -sheet, as the short α -helix H1 unfolds, thereby forming PrPsc [121, 122]. We have summarized the major characteristics of neurodegenerative diseases in Table 1. 2. POSSIBLE THERAPEUTICS Recent progress in the development of therapeutics for the treatment of neurodegenerative diseases currently stands at a promising juncture. We have summarized the neurodegenerative drug discovery efforts utilized by the scientific community throughout the globe, and simultaneously, focus on some of the most common targets, mechanisms, strategies, and pathways involved. 2.1. Inhibition of Amyloid Formation Nearly 30 human proteins are presently associated with either systemic or localized amyloidosis, giving rise to intracellular amyloid-like deposits associated with a number of diseases including all common dementias and type II diabetes. Large elderly populations are affected with AD and PD, as detailed earlier. Inhibition of the aggregation process has

864 Current Protein and Peptide Science, 2018, Vol. 19, No. 9

Table 1.

Fatima et al.

Summary of characterisitics of major neurodegerative diseases. Amyloid protein

Microscopic lesions

Clinical features

Affected regions of brain

Cellular location of aggregates

Proposed function of normal proteins


Amyloid β and Tau

Amyloid plaque, Neurofibrillary tangle, Lewy bodies

Progressive dementia

Hippocampus, Cerebral cortex

Extra-cellular Cytoplasmic

Neutrite outgrowth and Synaptic vesicle transport


α Synuclein

Lewy bodies

Movement disorders

Substantia nigra, Hypothalamus


Unknown function



Neuronal inclusions

Dementia, Motor and psychiatric problems

Striatum, Cerebral cortex


Transcriptional regulation


Superoxide dismutase

Hyaline inclusions

Movement disorders

Motor cortex, Brain stem


Antioxidant enzyme



Spinocerebral ataxia

Dementia with lewy bodies

Progressive supra nuclear palsy

Pe N rs ot on fo al rD U is se tri O bu n tio ly n


Protease resistant prion protein

Oligomers and plaques

Dementia, Ataxia, psychiatric problems

Various regions depending on the disease


Signal transduction, Antioxidant, Cu-binding

Hyperphosphorylated tau

Pick bodies

Dementia and loss of language

Dentate gyrus, Hippocampus, Neocortex


Stabilize microtubules


Polyglutamine (polyQ)

Involuntary motion of eyeball, absence of neurologic reflexes



Transcription coregulator

α Synuclein

Lewy bodies

Progressive dementia, Visual hallucinations

Substantia nigra, Hypothalamus


Unknown function


Tau positive inclusions

Progressive palsy, Movement disorders

Nerve cell clusters (Nuclei)


Stabilize microtubules

been a focused area of research and successful results have been obtained. Thus, the mechanism of amyloid formation itself offers several possibilities for therapeutic interventions. For example, the native structure can be stabilized by ligand binding or the monomeric peptide can be sequestered from further aggregation by binding to the protein. Also, supplementation of aggregate binding molecules aimed at directing oligomer formation into a nonproductive (non-pathogenic) aggregate, blockage of fibrils or disaggregation of fibrils, and plaque removal [123]. Thus, in many of these cases, the cytotoxic states can be averted and clearance of aggregates can be increased.

Familial amyloid polyneuropathy (FAP), a rare systemic amyloid disease characterized by endoneurial amyloid deposits, axonal degeneration, and neuronal loss [124]. Mutations in transthyretin (TTR), a tetrameric protein carrier of thyroid hormone causes FAP. It was proposed that FAP could be treated by stabilizing TTR tetramer via smallmolecule inhibitors (Fig. 3) [125]. Tafamidis meglumine was obtained through rational drug designing as one such compound [126] and was subjected to clinical trials. Phase II/III trials have been successfully completed. Approval of the drug would result in the first anti-amyloid drug in practice. 2.3. Potential Therapeutics of Aβ Amyloidosis

2.2. Native-state Stabilization A molecule that binds to the native state will increase the population of this state relative to other states according to the law of mass of action. This forms the thermodynamic basis of the protein folding–unfolding equilibrium. Small molecules or proteins/peptide that can bind to a protein’s native folded state can thus constrain it from unfolding and aggregation (by protecting the folded population and consequently decreasing the rate of unfolding).

2.3.1. β-Secretase and γ-Secretase Inhibitors The cleavage of APP results in the formation of Aβ fragment which is an important origin of aggregation, hence it could be effective drug targets. Interestingly, BACE betasite APP-cleaving enzyme) knock-out in mice has been reported to inhibit Aβ production without side effects. BACE inhibitors which include renin and HIV protease inhibitors have been developed and their crystal structures have been

Emerging Targets and Latest Proteomics Based Therapeutic

Current Protein and Peptide Science, 2018, Vol. 19, No. 9




Cl O N Cl

Pe N rs ot on fo al rD U is se tri O bu n tio ly n

Fig. (3). Structural characterization of transthyretin-tafamidis complex. (A) Structure of native, tetrameric TTR in complex with 2-(3,5dimethylphenyl) benzoxazole (Protein Data Bank ID: 2QGE). Inhibitor was shown to bound in two symmetrical thyroxine binding sites. (B) Chemical structure of tafamidis. It functions by kinetic stabilization of the correctly folded tetrameric form of the transthyretin (TTR) protein.

solved. They could thus possibly be good drugs for treating amyloidosis [127-130]. However, development of smallmolecule BACE inhibitors is difficult as the active-site of the enzyme is large and more exposed compared to other aspartyl proteases.

nization were ceased because of serious side-effects such as meningoencephalitis [139]. Active and passive immunization strategies with decreased side effects are currently under preclinical and clinical stages [137].

The APP γ-secretase has been an active target and some effective inhibitors have been developed [131]. For instance, Phase I trials with a γ -secretase inhibitor (LY450139) has been reported to reduce blood levels of Aβ [41], without affecting Aβ in CSF. Similarly, inhibitors of glycogen synthase kinase 3 (GSK3), such as lithium and kenpaullones as well as small interfering RNAs directed against GSK3α, reduce Aβ production in the cells in transgenic mice by inhibiting γ-secretase cleavage [132].

2.5. Nonsteroidal Anti-Inflammatory Drugs (NSAIDS)

2.4. Antibody Therapy and Vaccination

High cholesterol levels are proposed to elevate AD pathology. Surprisingly, statins or cholesterol lowering drugs were reported to reduce the AD risk by more than 70% in some cases [142]. This encouraged further investigation of statins on AD. Some studies reported improvement in cognitive function with reduced Aβ40 in the CSF with simvastatin. Large scale trial, however, did not show positive results [143].

Monoclonal antibodies raised by passive immunization against critical regions of the amyloid-β were reported to improve the cognitive function and other amyloid pathological effects after multiple injections into transgenic mice (as models for AD) expressing human APP [133, 134]. Active immunization of Aβ42 in a transgenic mouse model overexpressing human APP also generated anti-Aβ antibodies that averted Aβ plaque formation in young animals and moderated Aβ-related neuropathological changes and improved cognitive functions in old animals [135]. Thus, the immunotherapic targeting of Aβ has been particularly successful for both active and passive immunization, and many antibodies are currently in the late stages of clinical trials [136, 137]. The positive effects of anti-Aβ immunotherapy in vivo may be attributed to the mechanism of action. For example, the peripheral sink hypothesis proposes that the binding of antibodies to monomeric Aβ in blood alters the equilibrium and transport of Aβ over the blood brain barrier (BBB). Therefore, antibodies that cross the BBB into the CNS might interfere directly with the aggregation process of Aβ. It is also proposed that the antibodies that recognize amyloid fibrils trigger clearance of plaque via Fc-mediated phagocytosis [123, 138]. However, trials in human with active Aβ immu-

Several NSAIDs selectively lower Aβ42 through a mechanism involving the modulation of γ -secretase [140]. Preclinical studies on the R enantiomer of the NSAID reduce Aβ42 levels both in vitro and in vivo, and also decreased Aβ amyloid pathology in the brain [141]. However, these failed in phase III clinical trials. 2.6. Statins

2.7. Small-Molecule Inhibitors of Protein Aggregation and Possible Mechanism of Action Some small molecules can act as drugs to prevent misfolding of proteins. For example, Congo red (CR) (a hydrophilic symmetrical sulfonated azodye) binds to the β -sheet and thereby inhibits protein misfolding and consequently prevents Aβ aggregation and reduces in vivo toxicity [144]. CR also promotes the clearance of expanded (polyQ)containing aggregates both in vivo and in vitro in HD [145]. Several derivatives of CR, as well as thioflavin S, chrysamine G and direct fast yellow, are effective inhibitors of htt aggregation that acts in a dose-dependent manner [146]. Methylene blue is another such molecule known to reduce Aβ [147] as well as tau aggregation [148, 149]. However, the

866 Current Protein and Peptide Science, 2018, Vol. 19, No. 9

actual mechanism of action has been controversial, although the drug has entered clinical trials (Phase II).

amyloid deposition [177]. Tiwari et al., 2014 [172] found that Curcumin loaded PLGA Nanoparticles (NPs) induced adult neurogenesis very effectively and reversed cognitive deficits in a rat model. Curcumin, a non-flavonoidic polyphenol derived from the yellow curry spice, displays antiinflammatory and antioxidant activities. It is cytoprotective and induces nuclear translocation of HSF1 and its activation through the extracellular regulated kinase (ERK)/mitogen activated protein (MAP) and c-jun N-terminal kinase (JNK) pathways. Nonspecific inhibitors of protein aggregation selfassociate and form supramolecular structures. For instance, Congo red and lacmoid (common aggregation modulators) form supramolecular structure and inhibit aggregation of Aβ and α -synuclein90 [179, 180]. Thus, the mechanisms of action for many common anti-amyloid compounds might resemble those of detergents [181] and amphipathic molecules [182] which could possibly explain their broad specificity.

Pe N rs ot on fo al rD U is se tri O bu n tio ly n

Screening of drugs that reduce misfolding and aggregation/amyloid fibrils formation has extensively been done. Recently, a library of 200,000 compounds was screened for the inhibition of transformation of paired helical filament of tau protein to beta-sheet structure [150]. Out of these, 77 compounds classified on the basis of their chemical structure are N-phenylamines, anthraquinones, phenylthiazolyl hydrazides, and thioxothiazolidinones (rhodandines). These drugs were further chosen for the detailed investigation and structure–activity relationship (SAR) was carried out [123, 151]. Inositols, inhibitors of Aβ aggregation are one such example. The inhibitory effect has been reported to depend strongly on the stereo isomerization and the distribution of hydroxyl groups on the surface of the inositol scaffold [152, 153]. The myo-, scyllo-, and epi-inositol inhibited the formation of β -sheet structure and nontoxic oligomers of Aβ42. SAR analysis also established that the substitutions or deletions of hydroxyl groups in scyllo-inositol derivatives reduced their capacity to lessen fibril formation [154]. Lately, inositol glycans and d-chiro-inositol (DCI), have been investigated as potential candidates for AD therapeutics by protecting CNS synapses against Aβ oligomers through their insulin mimetic activity [155].

Fatima et al.

In a similar vein, screening of approximately 184,000 compounds was performed by an automated filter retardation assay to identify inhibitors of Huntingtin aggregation [156]. Twenty-five benzothiazole derivatives were found to retard aggregation of the protein. However, the in vivo results in mice were not very encouraging [157]. Discovery of (−)epigallocatechingallate (a polyphenol found in green tea) after some time fetched highly positive results. It proved to be a potent inhibitor of aggregation of Huntingtin, αsynuclein, amyloid β, amyloid related HIV infection and fibrillation κ -casein [158-161]. Dietary intake of polyphenols is known to attenuate oxidative stress and reduce the risk of AD, PD, HD, stroke and multiple sclerosis (MS). Polyphenols exhibit strong potential to address the etiology of neurological disorders as they attenuate their complex physiology by modulating several therapeutic targets at once [162, 163].

Diverse organic compounds have also been found to inhibit or reduce the aggregation of Aβ into fibrils in vitro [164]. These include nicotine [165], β -cyclodextrin derivatives [166], hemin and related porphyrins [167], 2, 4dinitrophenol [168], di- and trisubstituted aromatic molecules [169], anthracycline 4-iodo-4-deoxydoxorubicin [170], hexadecyl-N-methylpiperidinium (HMP) bromide [171], curcumin [172], hematin [173], meclocycline [174], indomethacin [175], melatonin [176] and rifampicin [177]. Umada et al., 2016 [178] tested rifampicin, curcumin, epigallocatechin-3-gallate, myricetin, and scyllo-inositol, in cells expressing APP with the Osaka (E693Δ) mutation, which promotes amyloid-β oligomerization. Rifampicin showed the strongest activities against the accumulation and toxicity of intracellular amyloid-β oligomers. Under cell-free conditions, rifampicin inhibited oligomer formation of amyloid-β, tau, and α-synuclein, indicating its broad spectrum. It is hypothesized to act via radical scavenger activity to inhibit

In the case of some specific inhibitors, for example, the effect of polyphenols on α -synuclein aggregation, the mechanism of action involves several aspects including oxidation reactions and covalent modification [183]. Direct correlation between the binding affinity of the compounds and aggregate inhibition is not found, instead, their involvement in oxidation, potential covalent modifications, and stabilization of oligomeric states of α-synuclein is hypothesized [123, 183]. SAR analysis suggested that the arrangement of hydroxyl groups on the flavonoid scaffold played a vital role [184]. 2.8. Molecular Chaperones Prevent Neurodegenerative Diseases The neuronal proteins are expected to be more susceptible to undergo cumulative misfolding because they are a long-lived protein that undergoes slow regeneration. Therefore, the capacity of neuronal chaperones to reduce misfolded proteins is essential to maintain neuronal integrity [185]. Moreover, most neurodegenerative diseases are characterized by typical misfolded protein aggregates, which strongly co-localize with molecular chaperones. In the case of PD, Hsp70 and Torsin A (protein homologous to yeast Hsp104), co-localize with α-synuclein containing Lewy bodies [186]. Hsp70 is known to bind prefibrillar oligomers and thereby inhibit aggregation and toxicity of synuclein [187]. Mutations in the oncogene DJ-1 are associated with familial PD, causing mitochondrial degeneration and oxidative stress which ultimately led to protein aggregation and neuronal cell death [188]. But DJ-1 and its mutants are known to associate with Hsp70, CHIP (chaperone interacting protein) and mtHSP70/Grp75 [189]. Since stress chaperones play a vital role in the pathogenesis of PD, it is important to note that the levels of HSPs decrease significantly with aging, which led to failure in cellular protein homeostasis, giving rise to such neurodegenerative diseases [190]. Studies in Drosophila have reported that overexpression of Hsp70 averts dopaminergic neuronal loss (caused by synuclein overexpression) while its inhibition led to synuclein toxicity [17]. The possible mechanism of Hsp70mediated protection comprises the involvement of misfolded

Emerging Targets and Latest Proteomics Based Therapeutic

proteins as substrates for parkin E3 ubiquitin ligase and degradation of aberrant synuclein [191]. Hsp90 along with a high level of insoluble α-synuclein was recently shown to be significantly increased in PD compared to age-matched controls. The increase in the expression of Hsp90 was also observed in a α-synuclein mutant transgenic mouse model of PD [185].

As discussed earlier, overexpression of Hsp40 and Hsp70 can reduce polyQ toxicity and inclusion body formation [200]. Also, overexpression of Hsp27 is suggested to reduce polyQ toxicity by reducing oxidative stress without affecting inclusion body formation [201]. In yeast, overexpression of Ssa1 (Hsp70) or Ydj1 (an Hsp40 homolog) significantly reduced the formation of large, detergent-insoluble inclusion bodies and facilitates the formation of smaller aggregates [202]. Co-expression of human Hsp70 averted lethality in Drosophila caused by the expression of truncated ataxin 3 with a poly Q expansion (MJDtr-Q78) [203]. Overexpression of Hsp70 in spinocerebellar ataxia 1 homolog (SCA1) transgenic mice (Ataxin1 with 82 polyQ repeats) improved the behavioral and pathological conditions significantly, without causing any change in inclusion body formation [204]. Thus, it could said that inclusion body may not be associated with toxicity. 3. CHEMICAL CHAPERONES Chemical chaperones are low molecular weight compounds that stabilize protein conformations against thermal and chemical denaturation, without actually binding to them. Its role in inhibiting the formation of misfolded structures and help to correct folding defects has been suggested [205]. The most common chemical chaperones used to promote folding are osmolytes such as glycerol and trimethylamineN-oxide (TMAO). They stabilize proteins by increasing their hydration, which in turn increases the surface area and the overall compactness of the native structure [206]. Osmolytes also reduce the free movement of proteins, thus preventing aggregation of partially folded species [207]. These have been shown to reverse the intracellular retention of several


different misfolded proteins such as CFTR [208], α antitrypsin [209], aquaporin-2 [210], vasopressin V2 receptor [211], α-galactosidase A [212], p53 [213] and Pglycoprotein [214]. Deuterated water might also function in a similar manner to promote protein folding [207]. In fact some of the chemical chaperones have been reported to correct folding and trafficking defects in cell culture models which include the mutant phenotype of the delta F508 cystic fibrosis transmembrane (TM) conductance regulator protein, DF508 CFTR (corrected by osmolytes glycerol and trimethylamine N-oxide, as well as deuterated water) in CF [215]. Also, CL4 (cytoplasmic loop 4) connecting TMs 10 and 11 is a ‘hot-spot' for CFTR processing mutations. The chemical chaperone CFcor-325 (4-cyclohexyloxy-2-{1-[4(4-methoxy-benezenesulphonyl) piperazin-1-yl]-ethyl}quinazoline) rescues most CL4 mutants [216]. Not all chemical chaperones function as osmolytes. Compounds such as dimethylsulphoxide, 4-phenyl butyrate, and lipids/detergents are not osmolytes but can promote folding of mutant proteins [207].

Pe N rs ot on fo al rD U is se tri O bu n tio ly n

Other chaperones have also been strongly implicated in AD pathology. For example, HSP27 and HSP70 are elevated in affected areas, partly due to gliosis and stressed neurons [192, 193]. Also during its normal processing in the ERGolgi pathway, APP interacts with the ER isoform of Hsp70 chaperone, BiP/Grp78 [194]. Increased Grp78 may assist proper processing of APP hence to reduce amyloid production. Also, overexpression of cytosolic Hsp70 and Hsp90 has been shown to inhibit early stages of amyloid aggregation [195]. It has also been established that small HSPs such as Hsp22 and Hsp27 bind to fibrillar amyloid plaques and inhibit fibrillarization [196]. In C. elegans, overexpression of the small Hsp16.2 has been found highly protective against Aβ-induced toxicity [197]. Chaperones involved in tau aggregation and fibrillization include Hsp27, Hsp70, and CHIP. This co-localize with abnormal tau aggregates and overexpression of these chaperones decreases hyperphosphorylation and escalates misfolded tau degradation [198]. Also, increased Hsp70 and Hsp90 levels promote tau solubility and enhanced its binding to microtubules in various cellular models [199].

Current Protein and Peptide Science, 2018, Vol. 19, No. 9

Effective therapy employing a chaperone system has not yet been established in AD. Peptidomimetics, based on the peptide LVFFA from Aβ, modified at the N- or C-terminus, and all-right-handed versions are known to block Aβ seeding and growth [217, 218]. However, the pharmacological profiles of these compounds are not encouraging. Nonpeptidic, aromatic-rich Aβ aggregation inhibitors have also been reported [219] and many pharmaceutical and biotechnology companies have tried it, but they lack specificity. The drugs currently in different stage of development against neurodegenerative diseases has been summarized in Table 2.

3.1. Food Habits

Since the majority of neurodegenerative diseases are known to have a sporadic origin, it is likely that the environmental factors play crucial roles in these diseases. Epidemiological studies have suggested the influence of dietary habits especially the intake of antioxidants on the occurrence and manisfestation of neurodegenerative disorders such as AD and PD are highly beneficial [220, 221]. Interestingly, an 80% reduction in dementia and AD was reported by the intake of 4 glasses of wine for three years as compared to age matched controls [222]. Also, consumption of the Ginkgo biloba extracts EGb 761 has been reported to improve cognitive performance in patients suffering from AD [223]. Tea, coffee, and caffeine are also known to reduce the risk of PD. A study by Qi and Li, 2014 reported a linear doserelationship for decreased PD risk with tea and caffeine consumption, and a maximum strength of protection at approximately 3 cups/day for coffee consumption [224]. Green tea is a beverage prepared from the leaves (steamed and dried) of the Camellia sinesis plant and contains strong antioxidant and neuroprotective phenolic compounds, the most important being (-)-Epigallocatechin-3-gallate [225]. Studies have shown a reduction in neurodegenerative diseases by increased flavonoid and polyphenols intake in populations above 65 years [226]. Polyphenols are natural substances found in green vegetables, fruits, plants and processed foods including olive oil, red wine, and tea. Flavonoids form the largest group of polyphenols. The polyphenols are rich in

868 Current Protein and Peptide Science, 2018, Vol. 19, No. 9

Table 2.

Fatima et al.

Developmental status of various drugs of neurodegerative diseases.



Developmental status


Amyloid β aggregation

Phase II completed

3APS (Alzhemed)

Amyloid β aggregation

Phase III clinical trial

Serum amyloid A amyloidosis

Phase III clinical trial


γ-secretase modulator

Failed in Phase III trials


Amyloid-β fibrillarization and disassembly of fibrils

Phase I


β-secretase APP cleaving enzyme



γ-secretase APP cleaving enzyme

Failed in Phase III trail

γ-secretase inhibitor

Failed in Phase III trail

I: Small compounds targeting amyloid formation

Eprodisate (KIACTA)

Pe N rs ot on fo al rD U is se tri O bu n tio ly n

MPC-7869 (Tarenflurbil) II: Immunotherapeutics

MAb binds to and clears amyloid-β

Failed in Phase III trail

Amyloid-β (vaccine)

Phase II trial


Phase II trial

Amyloid β aggregation

phase II completed

Cholinesterase inhibitors


Rivastigmine (Exelon)

Cholinesterase inhibitors


Galantamine (Razadyne)

Cholinesterase inhibitors


N-Methyl-D-aspartate (NMDA) antagonist


AAB-001(Bapineuzumab) CAD-106 ACC-001

III: Metal-protein interaction attenuation PBT2 (8-hydroxy quinoline)

IV. Currently approved Treatments for AD Donepezil (Aricept)

Memantine (Namenda)

antioxidants and reduce oxidative damages and toxic free radicals [162]. Some polyphenols have been reported to stimulate the stress response and increase cellular chaperone levels directly. For example, resveratrol (polyphenol from red wine) upregulate chaperones like Hsp70 in C0S-7 (African green monkey kidney fibroblast-like) cell lines and human peripheral lymphocytes [227]. Low doses of curcumin (non-flavonoidic polyphenol) led to 32% reduction in insoluble amyloid β plaque and a 43% reduction in soluble Aβ [228]. This effect is similar to that of aspirin [229]. 3.2. Rational Drug Designing

As a great deal of information regarding the structures of drugs is now available, a more rational approach to design small molecule ligands is possible. Essential to this process of drug development is the identification of disease-related molecules that can be targeted. Also, in-depth understanding of the pathophysiology will surely lead to the designing of the efficient drug for the treating neurodegenerative diseases. Drugs that can slow down, delay, or stop the onset of the disease are now being sought. A large number of screening protocols are already being practiced. For example, a fusion construct of Aβ42 and green fluorescent protein in a cell-

based assay allowed effective screening of large libraries.An important feature of this assay is the ability to identify inhibitors of early steps of the aggregation process, oligomers, which are more cytotoxic in nature [230]. A step further, a screening approach based on small-molecule microarrays was devised to identify ligands of fluorescently labeled monomeric Aβ40 [231]. Interestingly, out of the 79 hits from the assay, 15 compounds were found to reduce Aβ42induced cytotoxicity. Structural models for the interaction between Aβ and tau in their amyloid state with small molecules and co-crystallization of small peptide fragments with these compounds have been reported [232]. Advances towards a molecular understanding of the interactions between monomeric, intrinsically disordered proteins and smallmolecule aggregation inhibitors have also been made. The interaction between α-synuclein and dopamine (interferes with its aggregation) have been investigated using molecular dynamics simulations [233]. Also, the search for reliable, easy to detect and clinically relevant markers for the onset of the disease is being sought. 3.3. Latest Proteomics Based Therapies Proteomic based approaches have recently been undertaken to augment the specificity of diagnosis and treatment

Emerging Targets and Latest Proteomics Based Therapeutic


Neurodegenerative disorders are multifactorial in nature and involve multiple biological processes, which may require equally complex approaches to treatment. While there is a strong association between protein aggregation, inclusion formation and neuronal dysfunction and death, the mechanistic relationship between each of them remains one of the biggest questions in the field. What is clear is that proteostasis collapse is a critical part of this process that can be caused by the burden of pathogenically misfolded proteins or peptides. In contrast, as was the focus of this review, proteostasis imbalance can be caused by dysfunction in pathways that maintain proteostasis such as molecular chaperones and protein degradation and this may contribute to both protein aggregation and neurodegeneration. Regardless, increasing the capacity of the proteostasis network will be an important area of future research. The antibody therapy, delivery of two or more compounds directed against these targets, along with the design of small molecules with multiple modes of action should be explored in pursuit of more effective clinical treatments for neurodegenerative diseases. A more holistic approach to understanding proteostasis in the context of


neurodegenerative diseases will, therefore, be important for future research. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENTS Declared none. REFERENCES [1] [2]

Hartl, F.U.; Bracher, A.; Hayer-Hartl, M. Molecular chaperones in protein folding and proteostasis. Nature, 2011, 475, 324-332. Arai, M.; Kuwajima, K. Role of the molten globule state in protein folding. Adv. Prot. Chem., 2000, 53, 209-282. Schartz, G. The protein import machinery of mitochondria. Protein Sci., 1993, 2, 141-146. Ellis, R.J.; Minton, A.P. Protein aggregation in crowded environments. Biol. Chem., 2006, 387, 485-497. Dunker, A.K.; Silman, I.; Uversky, V.N.; Sussman, J.L. Function and structure of inherently disordered proteins. Curr. Opin. Struct. Biol., 2008, 18, 756-764. Powers, E.T.; Morimoto, R.I.; Dillin, A.; Kelly, J.W.; Balch, W.E. Biological and chemical approaches to diseases of proteostasis deficiency. Annu. Rev. Biochem., 2009, 78, 959-991. Hartl, F.U. Molecular chaperones in cellular protein folding. Nature, 1996, 381, 571-579. Tillement, J.P.; Lecanu, L.; Papadopoulos, V. Amyloidosis and neurodegenerative diseases: Current treatments and new pharmacological options. Pharmacology, 2010, 85, 1-17. Nagai, Y.; Fujikake, N.; Popiel, H.A.; Wada, K. Induction of molecular chaperones as a therapeutic strategy for the polyglutamine diseases. Curr. Pharm. Biotechnol., 2010, 11, 188197. Balch, W.E.; Morimoto, R.I.; Dillin, A.; Kelly, J.W. Adapting proteostasis for disease intervention. Science, 2008, 319, 916-919. Hartl, F.U.; Hayer-Hartl, M. Converging concepts of protein folding in vitro and in vivo. Nat. Struct. Mol. Biol., 2009, 16, 574581. Westerheide, S.D.; Morimoto, R.I. Heat shock response modulators as therapeutic tools for diseases of protein conformation. J. Biol. Chem., 2005, 280, 33097-33100. Mu, T.W.; Ong, D.S.T.; Wang, Y.J.; Balch, W.E.; Yates, J.R.; Segatori, L.; Kelly, J.W. Chemical and biological approaches synergize to ameliorate protein-folding diseases. Cell, 2008, 134, 769-781. Calamini, B.; Silva, M.C.; Madoux, F.; Hutt, D.M.; Khanna, S.; Chalfant, M.; Saldanha, S.A.; Hodder, P.; Tait, B.D.; Garza, D.; Balch, W.E.; Morimoto, R.I. Small-molecule proteostasis regulators for protein conformational diseases. Nat. Chem. Biol., 2011, 8, 185-196. Schaffar, G.; Breuer, P.; Boteva, R.; Behrends, C.; Tzvetkov, N.; Strippel, N.; Sakahira, H.; Siegers, K.; Hayer-Hartl, M.; Hartl, F.U. Cellular toxicity of polyglutamine expansion proteins: Mechanism of transcription factor deactivation. Mol. Cell, 2004, 15, 95-105. Lotz, G.P.; Legleiter, J.; Aron, R.; Mitchell, E.J.; Huang, S.Y.; Ng, C.; Glabe, C.; Thompson, L.M.; Muchowski, P.J. Hsp70 and Hsp40 functionally interact with soluble mutant huntingtin oligomers in a classic ATP-dependent reaction cycle. J. Biol. Chem., 2010, 285, 38183-38193. Auluck, P.K.; Chan, H.Y.E.; Trojanowski, J.Q.; Lee, V.M.-Y.; Bonini, N. Chaperone suppression of a-synuclein toxicity in a drosophila model for Parkinson’s disease. Science, 2002, 295, 865868. Hageman, J.; Rujano, M.A.; van Waarde, M.A.W.H.; Kakkar, V.; Dirks, R.P.; Govorukhina, N.; Oosterveld-Hut, H.M.J.; Lubsen, N.H.; Kampinga, H.H. A DNAJB chaperone subfamily with

Pe N rs ot on fo al rD U is se tri O bu n tio ly n

of the disease, particularly in the area of neuropathologies. Altered levels of proteins in several biological fluids can reflect pathological changes in the brain or spinal cord, thus allowing better understanding of both the disease and therapies implemented. Proteomics based diagnosis of these disorders play a crucial role in unravelling the molecular mechanism and hence their treatment. The major techniques include methods based on (1) antibody analysis which includes assays that recognize specific protein epitope or antigen by monoclonal antibody and involve (i) Immunohistochemistry, (ii) protein assays like enzyme-linked immune sorbent assay (ELISA) and protein array, and (iii) immunoprecipitation of specific proteins and their complexes (2) peak-profiling mass Spectrometry. Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) was applied to the cerebrospinal fluid (CSF) in a population of healthy controls and of AD/ frontotemporal dementian (FTD) patients. Thirty candidate biomarkers were identified in which seven differentiated well between AD and FTD. Specifically, the 8-amino acid truncation of cystatin C proved as the best marker distinctly differentiating AD from healthy controls and FTD [234]. More advanced techniques, such as matrix-assisted laser desorption/ionization (MALDI), have been used to localize particular aggregates of mutated SOD1 in the mSOD1 mouse model [235]. and (3) traditional gel-based procedures including one dimensional gel electrophoresis (1DE) and 2DE and differential imaging gel electrophoresis (DIGE), a variant of 2DE [236]. Personalized proteomics for clinical analysis of fluid biopsy specimens also offers a new diagnostic and therapeutic approach for patient-specific therapies [237]. Protein expression is dynamic and correlates to the disease timing, severity, and response to therapy. This, in turn, is helpful in the identification of key molecular constituents and a highly specific targeting, increasing patient’s compliance and dealing with, or at least greatly minimizing the side-effects of conventional medicine based systems.

Current Protein and Peptide Science, 2018, Vol. 19, No. 9

[3] [4]















870 Current Protein and Peptide Science, 2018, Vol. 19, No. 9

[20] [21]






[27] [28]


[30] [31]

[32] [33]


[35] [36]



[39] [40]


[42] [43] [44] [45] [46] [47]

Selkoe, D.J. Translating cell biology into therapeutic advances in Alzheimer’s disease. Nature, 1999, 399, A23-A31. Gaggelli, E.; Kozlowski, H.; Valensin, D.; Valensin, G. Copper homeostasis and neurodegenerative disorders (Alzheimer’s, prion, and Parkinson's diseases and amyotrophic lateral sclerosis). Chem. Rev., 2006, 106, 1995-2044. Skovronsky, D.M.; Lee, V.M.; Trojanowski, J.Q. Neurodegenerative diseases: New concepts of pathogenesis and their therapeutic implications. Annu. Rev. Pathol., 2006, 1, 151-170. Esler, W.P.; Wolfe, M.S. A portrait of Alzheimer’s secretases New features and familiar faces. Science, 2001, 293, 1449-1454. Citron, M. Alzheimer’s disease: Treatments in discovery and development. Nat. Neurosci., 2002, 5(Suppl), 1055-1057. Rosenberg, R.N. The molecular and genetic basis of AD: The end of the beginning: The 2000 wartenberg lecture. Neurology, 2000, 54, 2045-2054. Dobson, C.M. Protein misfolding, evolution and disease. Trends Biochem. Sci., 1999, 24, 329-332. Dobson, C.M. (CUL-ID:1481556) Protein folding and misfolding. Nature, 2003, 426, 884-890. Higuchi, M.; Iwata, N.; Saido, T.C. Understanding molecular mechanisms of proteolysis in Alzheimer’s disease: Progress toward therapeutic interventions. Biochim. Biophys. Acta, 2005, 1751, 6067. Hilbich, C.; Kisters-woike, B.; Reed, J.; Masters, C.L.; Beyreuther, K. Substitutions of hydrophobic amino acids reduce the amyloidogenicity of Alzheimer’s disease PA4 peptides. J. Mol. Biol., 1992, 228, 460-473. Soto, C.; Castaño, E.M.; Frangione, B.; Inestrosa, N.C. The alphahelical to beta-strand transition in the amino-terminal fragment of the amyloid beta-peptide modulates amyloid formation. J. Biol. Chem., 1995, 270, 3063-3067. Jarrett, J.T.; Berger, E.P.; Lansbury, P.T. The C-terminus of the beta-protein is critical in amyloidogenesis. Ann. N. Y. Acad. Sci., 1993, 695, 144-148. Otzen, D.E.; Kristensen, O.; Oliveberg, M. Designed protein tetramer zipped together with a hydrophobic alzheimer homology: A structural clue to amyloid assembly. Proc. Natl. Acad. Sci. USA, 2000, 97, 9907-9912. Chiti, F.; Taddei, N.; Baroni, F.; Capanni, C.; Stefani, M.; Ramponi, G.; Dobson, C.M. Kinetic partitioning of protein folding and aggregation. Nat. Struct. Biol., 2002, 9, 137-143. Wurth, C.; Guimard, N.K.; Hecht, M.H. Mutations that reduce aggregation of the alzheimer’s Abeta42 peptide: An unbiased search for the sequence determinants of Abeta amyloidogenesis. J. Mol. Biol., 2002, 319, 1279-1290. Chiti, F.; Calamai, M.; Taddei, N.; Stefani, M.; Ramponi, G.; Dobson, C.M. Studies of the aggregation of mutant proteins in vitro provide insights into the genetics of amyloid diseases. Proc. Natl. Acad. Sci. USA, 2002, 99(Suppl 4), 16419-16426. Chiti, F.; Dobson, C.M. Protein misfolding, functional amyloid, and human disease. Annu. Rev. Biochem, 2006, 75, 333-366. Grundke-Iqbal, I.; Iqbal, K.; Quinlan, M.; Tung, Y.C.; Zaidi, M.S.; Wisniewski, H.M. Microtubule-associated protein Tau. A Component of Alzheimer paired helical filaments. J. Biol. Chem., 1986, 261, 6084-6089. Bezprozvanny, I.; Mattson, M.P. Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci., 2008, 31, 454-463. Fukazawa, R.; Hanyu, H.; Sato, T.; Shimizu, S.; Koyama, S.; Kanetaka, H.; Sakurai, H.; Iwamoto, T. Subgroups of Alzheimer’s disease associated with diabetes mellitus based on brain imaging. Dement. Geriatr. Cogn. Disord., 2013, 35, 280-290. Kopf, D.; Frolich, L. Risk of incident Alzheimer’s disease in diabetic patients: A systematic review of prospective trials. J. Alzheimers. Dis., 2009, 16, 677-685. Rivera, E.J.; Goldin, A.; Fulmer, N.; Tavares, R.; Wands, J.R.; de la Monte, S.M. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: Link to brain reductions in acetylcholine. J. Alzheimers. Dis., 2005, 8, 247-268. Janson, J.; Laedtke, T.; Parisi, J.E.; O’Brien, P.; Petersen, R.C.; Butler, P.C. Increased risk of type 2 diabetes in Alzheimer disease. Diabetes, 2004, 53, 474-481. Kroner, Z. The relationship between Alzheimer’s disease and diabetes: Type 3 diabetes? Altern. Med. Rev., 2009, 14, 373-379.

Pe N rs ot on fo al rD U is se tri O bu n tio ly n


HDAC-dependent activities suppresses toxic protein aggregation. Mol. Cell, 2010, 37, 355-369. Sunde, M.; Blake, C. The structure of amyloid fibrils by electron microscopy and X-ray diffraction. Adv. Protein Chem., 1997, 50, 123-159. Serpell, L.C.; Sunde, M.; Benson, M.D.; Tennent, G.A.; Pepys, M.B.; Fraser, P.E. The protofilament substructure of amyloid fibrils. J. Mol. Biol., 2000, 300, 1033-1039. Bauer, H.H.; Aebi, U.; Häner, M.; Hermann, R.; Müller, M.; Arvinte, T.; Merkle, H.P. Architecture and polymorphism of fibrillar supramolecular assemblies produced by in vitro aggregation of human calcitonin. J. Struct. Biol., 1995, 115, 1-15. Saiki, M.; Honda, S.; Kawasaki, K.; Zhou, D.; Kaito, A.; Konakahara, T.; Morii, H. Higher-order molecular packing in amyloid-like fibrils constructed with linear arrangements of hydrophobic and hydrogen-bonding side-chains. J. Mol. Biol., 2005, 348, 983-998. Petkova, A.T.; Ishii, Y.; Balbach, J.J.; Antzutkin, O.N.; Leapman, R.D.; Delaglio, F.; Tycko, R. A structural model for Alzheimer’s beta -amyloid fibrils based on experimental constraints from solid state NMR. Proc Natl Acad Sci U S A, 2002, 99, 16742-16747. Liu, C.; Zhao, M.; Jiang, L.; Cheng, P.-N.; Park, J.; Sawaya, M.R.; Pensalfini, A.; Gou, D.; Berk, A.J.; Glabe, C.G.; Nowick, J.; Eisenberg, D. Out-of-register β -sheets suggest a pathway to toxic amyloid aggregates. Proc. Natl. Acad. Sci. USA, 2012, 109, 2091320918. Serpell, L.C.; Smith, J.M. Direct visualisation of the β -sheet structure of synthetic Alzheimer’s amyloid. J. Mol. Biol., 2000, 299, 225-231. Skovronsky, D.M.; Lee, V.M.-Y.; Trojanowski, J.Q. Neurodegenerative diseases: New concepts of pathogenesis and their therapeutic implications. Annu. Rev. Pathol., 2006, 1, 151170. Guo, J.L.; Lee, V.M. Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases. Nat. Med., 2014, 20, 130138. Cacciatore, I.; Baldassarre, L.; Fornasari, E.; Mollica, A.; Pinnen, F. Recent advances in the treatment of neurodegenerative diseases based on GSH delivery systems. Oxid. Med. Cell Longev., 2012, 2012, 240146. Hebert, L.E.; Weuve, J.; Scherr, P.A.; Evans, D.A. Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology, 2013, 80, 1778-1783. Brookmeyer, R.; Johnson, E.; Ziegler-Graham, K.; Arrighi, H.M. forecasting the global burden of Alzheimer’s disease. Alzheimer’s Dement., 2007, 3, 186-191. United Nations, Department of Economic and Social Affairs, P.D. World Population Ageing 2015. World Population Ageing 2015, 2015. Brookmeyer, R.; Gray, S.; Kawas, C. Projections of Alzheimer’s disease in the United States and the public health impact of delaying disease onset. Am. J. Public Heal., 1998, 88, 1337-1342. Mayeux, R.; Stern, Y.; Ottman, R.; Tatemichi, T.K.; Tang, M.X.; Maestre, G.; Ngai, C.; Tycko, B.; Ginsberg, H. The apolipoprotein epsilon 4 allele in patients with Alzheimer’s disease. Ann. Neurol., 1993, 34, 752-754. Mahley, R.W.; Weisgraber, K.H.; Huang, Y. Apolipoprotein E: Structure determines function, from atherosclerosis to Alzheimer’s disease to AIDS. J. Lipid Res., 2009, 50(Suppl), S183-S188. Liu, C.-C.; Liu, C.-C.; Kanekiyo, T.; Xu, H.; Bu, G. Apolipoprotein E and Alzheimer disease: Risk, mechanisms and therapy. Nat. Rev. Neurol., 2013, 9, 106-118. Farrer, L.A.; Cupples, L.A.; Haines, J.L.; Hyman, B.; Kukull, W.A.; Mayeux, R.; Myers, R.H.; Pericak-Vance, M.A.; Risch, N.; van Duijn, C.M. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and alzheimer disease. A meta-analysis. APOE and Alzheimer disease meta analysis consortium. JAMA, 1997, 278, 1349-1356. Wang, J.M.; Irwin, R.W.; Brinton, R.D. Activation of estrogen receptor alpha increases and estrogen receptor beta decreases apolipoprotein E expression in hippocampus in vitro and in vivo. Proc Natl Acad Sci USA, 2006, 103, 16983-16988. Bu, G. Apolipoprotein E and its receptors in Alzheimer’s disease: Pathways, pathogenesis and therapy. Nat. Rev. Neurosci., 2009, 10, 333-344.

Fatima et al.












[59] [60]

[61] [62]

Emerging Targets and Latest Proteomics Based Therapeutic


[65] [66]

[67] [68] [69] [70]

[71] [72]




[76] [77] [78] [79] [80]



[83] [84]

[85] [86]

Li, Z.G.; Zhang, W.; Sima, A.A.F. Alzheimer-like changes in rat models of spontaneous diabetes. Diabetes, 2007, 56, 1817-1824. Planel, E.; Tatebayashi, Y.; Miyasaka, T.; Liu, L.; Wang, L.; Herman, M.; Yu, W.H.; Luchsinger, J.; Wadzinski, B.; Duff, K.E.; Takashima, A. Insulin dysfunction induces in vivo Tau hyperphosphorylation through distinct mechanisms. J. Neurosci., 2007, 27, 13635-13648. Kim, B.; Backus, C.; Oh, S.; Hayes, J.M.; Feldman, E.L. Increased Tau phosphorylation and cleavage in mouse models of type 1 and type 2 diabetes. Endocrinology, 2009, 150, 5294-5301. Wirdefeldt, K.; Adami, H.-O.; Cole, P.; Trichopoulos, D.; Mandel, J. Epidemiology and etiology of Parkinson’s disease: A review of the evidence. Eur. J. Epidemiol., 2011, 26(Suppl 1), S1-S58. Clarke, C.E. Parkinson’s disease. BMJ, 2007, 335, 441-445. Forno, L.S. Neuropathology of Parkinson’s disease. J. Neuropathol. Exp. Neurol., 1996, 55, 259-272. Davie, C.A. A review of Parkinson’s disease. Br. Med. Bull., 2008, 86, 109-127. Spillantini, M.G.; Schmidt, M.L.; Lee, V.M.; Trojanowski, J.Q.; Jakes, R.; Goedert, M. Alpha-synuclein in lewy bodies. Nature, 1997, 388, 839-840. de la Fuente-Fernández, R. Imaging of dopamine in PD and implications for motor and neuropsychiatric manifestations of PD. Front. Neurol., 2013, 4, 90. Warner, T.T.; Schapira, A.H. Genetic and environmental factors in the cause of parkinson’s disease. Ann. Neurol., 2003, 53(Suppl 3), S16-S23. Cookson, M.; Xiromerisiou, G.; Singleton, A. How genetics research in Parkinson’s disease is enhancing understanding of the common idiopathic forms of the disease. Curr. Opin. Neurol., 2005, 18, 706-711. Gilks, W.P.; Abou-Sleiman, P.M.; Gandhi, S.; Jain, S.; Singleton, A.; Lees, A.J.; Shaw, K.; Bhatia, K.P.; Bonifati, V.; Quinn, N.P.; Lynch, J.; Healy, D.G.; Holton, J.L.; Revesz, T.; Wood, N.W. A common LRRK2 mutation in idiopathic Parkinson’s disease. Lancet, 2005, 365, 415-416. Chung, K.K.; Zhang, Y.; Lim, K.L.; Tanaka, Y.; Huang, H.; Gao, J.; Ross, C.; Dawson, V.L.; Dawson, T.M. Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: Implications for lewy-body formation in Parkinson disease. Nat. Med., 2001, 7, 1144-1150. Schapira, A.H.V. Mitochondria in the aetiology and pathogenesis of Parkinson’s disease. Lancet Neurol., 2008, 7, 97-109. Dias, V.; Junn, E.; Mouradian, M.M. The role of oxidative stress in Parkinson’s disease. J. Parkinson’s Dis., 2013, 3, 461-491. Wang, X.; Michaelis, E.K. Selective neuronal vulnerability to oxidative stress in the brain. Front. Aging Neurosci., 2010, 2, 12. Dick, F.D. Parkinson’s disease and pesticide exposures. Br. Med. Bull., 2006, 79-80, 219-231. Bastías-Candia, S.; Di Benedetto, M.; D’Addario, C.; Candeletti, S.; Romualdi, P. Combined exposure to agriculture pesticides, paraquat and maneb, induces alterations in the N/OFQ-NOPr and PDYN/KOPr systems in rats: Relevance to sporadic parkinson’s disease. Environ. Toxicol., 2015, 30, 656-663. Bertoncini, C.W.; Jung, Y.-S.; Fernandez, C.O.; Hoyer, W.; Griesinger, C.; Jovin, T.M.; Zweckstetter, M. Release of longrange tertiary interactions potentiates aggregation of natively unstructured alpha-synuclein. Proc. Natl. Acad. Sci. USA, 2005, 102, 1430-1435. Fernández, C.O.; Hoyer, W.; Zweckstetter, M.; Jares-Erijman, E.A.; Subramaniam, V.; Griesinger, C.; Jovin, T.M. NMR of α Synuclein–polyamine complexes elucidates the mechanism and kinetics of induced aggregation. EMBO J., 2004, 23, 2039-2046. Cook, C.; Stetler, C.; Petrucelli, L. Disruption of protein quality control in Parkinson’s disease. Cold Spring Harb. Perspect. Med., 2012, 2, a009423. Bruyn, G.W. Huntington’s Chorea: Historical, Clinical and Laboratory Synopsis; Vinken, P.J.; Bruyn, G.W.; Ed.; Elsevier Inc.: Amsterdam, 1968; Vol. 6, pp. 298-378. Roos, R.A.C. Huntington’s disease: A clinical review. Orphanet J. Rare Dis., 2010, 5, 40. Harjes, P.; Wanker, E.E. The hunt for huntingtin function: interaction partners tell many different stories. Trends Biochem. Sci., 2003, 28, 425-433.








[94] [95]









Li, S.H.; Li, X.J. Huntingtin-protein interactions and the pathogenesis of Huntington’s disease. Trends Genet., 2004, 20, 146-154. Rigamonti, D.; Bauer, J.H.; De-Fraja, C.; Conti, L.; Sipione, S.; Sciorati, C.; Clementi, E.; Hackam, A.; Hayden, M.R.; Li, Y.; Cooper, J.K.; Ross, C.A.; Govoni, S.; Vincenz, C.; Cattaneo, E. Wild-type huntingtin protects from apoptosis upstream of caspase3. J. Neurosci., 2000, 20, 3705-3713. MacDonald, M.E.; Ambrose, C.M.; Duyao, M.P.; Myers, R.H.; Lin, C.; Srinidhi, L.; Barnes, G.; Taylor, S.A.; James, M.; Groot, N.; MacFarlane, H.; Jenkins, B.; Anderson, M.A.; Wexler, N.S.; Gusella, J.F.; Bates, G.P.; Baxendale, S.; Hummerich, H.; Kirby, S.; North, M.; Youngman, S.; Mott, R.; Zehetner, G.; Sedlacek, Z.; Poustka, A.; Frischauf, A.M.; Lehrach, H.; Buckler, A.J.; Church, D.; Doucette-Stamm, L.; O’Donovan, M.C.; Riba-Ramirez, L.; Shah, M.; Stanton, V.P.; Strobel, S.A.; Draths, K.M.; Wales, J.L.; Dervan, P.; Housman, D.E.; Altherr, M.; Shiang, R.; Thompson, L.; Fielder, T.; Wasmuth, J.J.; Tagle, D.; Valdes, J.; Elmer, L.; Allard, M.; Castilla, L.; Swaroop, M.; Blanchard, K.; Collins, F.S.; Snell, R.; Holloway, T.; Gillespie, K.; Datson, N.; Shaw, D.; Harper, P.S. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell, 1993, 72, 971-983. Wheelock, V.L.; Tempkin, T.; Marder, K.; Nance, M.; Myers, R.H.; Zhao, H.; Kayson, E.; Orme, C.; Shoulson, I. Predictors of nursing home placement in Huntington disease. Neurology, 2003, 60, 998-1001. Arrasate, M.; Finkbeiner, S. Protein aggregates in Huntington’s disease. Experimental Neurology, 2012, 238, 1-11. Sakahira, H.; Breuer, P.; Hayer-Hartl, M.K.; Hartl, F.U. Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity. Proc. Natl. Acad. Sci. USA, 2002, 99(Suppl 4), 1641216418. Hay, D.G.; Sathasivam, K.; Tobaben, S.; Stahl, B.; Marber, M. Progressive decrease in chaperone protein levels in a mouse model of Huntington's disease and induction of stress proteins as a therapeutic approach. Hum. Mol. Genet., 2004, 13, 1389-1405. Landles, C.; Bates, G.P. Huntingtin and the molecular pathogenesis of huntington’s disease. Fourth in molecular medicine review series. EMBO Rep., 2004, 5, 958-963. Cleveland, D.W. Mechanisms of selective motor neuron death in ALS. Neuron, 1999, 24, 515-520. Grad, L.I.; Cashman, N.R. Prion-like activity of Cu/Zn superoxide dismutase: Implications for amyotrophic lateral sclerosis. Prion, 2014, 8, 1-9. Neumann, M.; Sampathu, D.M.; Kwong, L.K.; Truax, A.C.; Micsenyi, M.C.; Chou, T.T.; Bruce, J.; Schuck, T.; Grossman, M.; Clark, C.M.; McCluskey, L.F.; Miller, B.L.; Masliah, E.; Mackenzie, I.R.; Feldman, H.; Feiden, W.; Kretzschmar, H.A.; Trojanowski, J.Q.; Lee, V.M.-Y. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science, 2006, 314, 130-133. Kwiatkowski, T.J.; Bosco, D.; Leclerc, L.; Tamrazian, E.; Vanderburg, C.R.; Russ, C.; Davis, A.; Gilchrist, J.; Kasarskis, E.J.; Munsat, T.; Valdmanis, P.; Rouleau, G.; Hosler, B.; Cortelli, P.; de Jong, P.J.; Yoshinaga, Y.; Haines, J.L.; Pericak-Vance, M.; Yan, J.; Ticozzi, N.; Siddique, T.; McKenna-Yasek, D.; Sapp, P.C.; Horvitz, H.R.; Landers, J.E.; Brown, R.H. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science, 2009, 323, 1205-1208. Banci, L.; Bertini, I.; Boca, M.; Calderone, V.; Cantini, F.; Girotto, S.; Vieru, M. Structural and dynamic aspects related to oligomerization of apo SOD1 and its mutants. Proc. Natl. Acad. Sci. USA, 2009, 106, 6980-6985. Forsberg, K.; Jonsson, P.A.; Andersen, P.M.; Bergemalm, D.; Graffmo, K.S.; Hultdin, M.; Jacobsson, J.; Rosquist, R.; Marklund, S.L.; Brännström, T. Novel antibodies reveal inclusions containing non-native SOD1 in sporadic ALS patients. PLoS One, 2010, 5, e11552. Kim, S.H.; Shanware, N.P.; Bowler, M.J.; Tibbetts, R.S. Amyotrophic lateral sclerosis-associated proteins TDP-43 and FUS/TLS function in a common biochemical complex to coregulate HDAC6 mRNA. J. Biol. Chem., 2010, 285, 34097-34105. Lagier-Tourenne, C.; Polymenidou, M.; Cleveland, D.W. TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. Hum. Mol. Genet., 2010, 19(R1), R46-R64.

Pe N rs ot on fo al rD U is se tri O bu n tio ly n


Current Protein and Peptide Science, 2018, Vol. 19, No. 9

872 Current Protein and Peptide Science, 2018, Vol. 19, No. 9


[105] [106]

[107] [108]

[109] [110]



[113] [114] [115]

[116] [117]

[118] [119]

[120] [121]

[122] [123] [124]


Dormann, D.; Rodde, R.; Edbauer, D.; Bentmann, E.; Fischer, I.; Hruscha, A.; Than, M.E.; Mackenzie, I.R. a; Capell, A.; Schmid, B.; Haass, C.; Neumann, M.; Haass, C. ALS-Associated Fused in Sarcoma (FUS) mutations disrupt transportin-mediated nuclear import. EMBO J., 2010, 29, 2841-2857. Moisse, K.; Volkening, K.; Leystra-Lantz, C.; Welch, I.; Hill, T.; Strong, M.J. Divergent patterns of cytosolic TDP-43 and neuronal progranulin expression following axotomy: Implications for TDP43 in the physiological response to neuronal injury. Brain Res., 2009, 1249, 202-211. Tabrizi, S.J.; Elliott, C.L.; Weissmann, C. Ethical issues in human prion diseases. Br. Med. Bull., 2003, 66, 305-316. Collinge, J.; Brown, J.; Hardy, J.; Mullan, M.; Rossor, M.N.; Baker, H.; Crow, T.J.; Lofthouse, R.; Poulter, M.; Ridley, R.; Owen, F.; Bennett, C.; Dunn, G.; Harding, A.E.; Quinn, N.; Doshi, B.; Roberts, G.W.; Honavar, M.; Janota, I.; Lantos, P.L. Inherited prion disease with 144 base pair gene insertion: 2. clinical and pathological features. Brain, 1992, 115, 687-710. Prusiner, S.B. Prions. Proc. Natl. Acad. Sci. USA, 1998, 95, 1336313383. Will, R.G.; Ironside, J.W.; Zeidler, M.; Cousens, S.N.; Estibeiro, K.; Alperovitch, A.; Poser, S.; Pocchiari, M.; Hofmar, A.; Smith, P.G. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet, 1996, 347, 921-925. Hetz, C.; Soto, C. Protein misfolding and disease: The case of prion disorders. Cell. Mol. Life Sci., 2003, 60, 133-143. Soto, C.; Saborío, G.P. Prions: Disease propagation and disease therapy by conformational transmission. Trends Mol. Med., 2001, 7, 109-114. Torres, M.; Castillo, K.; Armisén, R.; Stutzin, A.; Soto, C.; Hetz, C. Prion protein misfolding affects calcium homeostasis and sensitizes cells to endoplasmic reticulum stress. PLoS One, 2010, 5, e15658. Oesch, B.; Westaway, D.; Wälchli, M.; McKinley, M.P.; Kent, S.B.H.; Aebersold, R.; Barry, R.A.; Tempst, P.; Teplow, D.B.; Hood, L.E.; Prusiner, S.B.; Weissmann, C. A cellular gene encodes scrapie PrP 27-30 protein. Cell, 1985, 40, 735-746. Stahl, N.; Prusiner, S.B. Prions and prion proteins. FASEB J., 1991, 5, 2799-2807. Noinville, S.; Chich, J.F.; Rezaei, H. Misfolding of the prion protein: Linking biophysical and biological approaches. Vet. Res., 2008, 39(4), 48. Hegde, R.S.; Rane, N.S. Prion protein trafficking and the development of neurodegeneration. Trends Neurosci., 2003, 26, 337-339. Yedidia, Y.; Horonchik, L.; Tzaban, S.; Yanai, A.; Taraboulos, A. Proteasomes and ubiquitin are involved in the turnover of the wildtype prion protein. EMBO J., 2001, 20, 5383-5391. Ma, J.; Lindquist, S. Wild-type PrP and a mutant associated with prion disease are subject to retrograde transport and proteasome degradation. Proc. Natl. Acad. Sci. USA, 2001, 98, 14955-14960. Hetz, C.A.; Soto, C. Stressing out the ER: A role of the unfolded protein response in prion-related disorders. Curr. Mol. Med., 2006, 6, 37-43. Lysek, D.A.; Schorn, C.; Nivon, L.G.; Esteve-Moya, V.; Christen, B.; Calzolai, L.; von Schroetter, C.; Fiorito, F.; Herrmann, T.; Güntert, P.; Wüthrich, K. Prion protein NMR structures of cats, dogs, pigs, and sheep. Proc. Natl. Acad. Sci. USA, 2005, 102, 640645. López Garcia, F.; Zahn, R.; Riek, R.; Wüthrich, K. NMR structure of the bovine prion protein. Proc. Natl. Acad. Sci. USA, 2000, 97, 8334-8339. Morrissey, M.P.; Shakhnovich, E.I. Evidence for the role of PrP(C) helix 1 in the hydrophilic seeding of prion aggregates. Proc. Natl. Acad. Sci. USA, 1999, 96, 11293-11298. Jarrett, J.T.; Lansbury, P.T. Seeding “one-dimensional crystallization” of amyloid: A pathogenic mechanism in Alzheimer’s disease and scrapie? Cell, 1993, 73, 1055-1058. Härd, T.; Lendel, C. Inhibition of amyloid formation. J. Mol. Biol., 2012, 421, 441-465. Hou, X.; Aguilar, M.-I.; Small, D.H. Transthyretin and familial amyloidotic polyneuropathy. Recent progress in understanding the molecular mechanism of neurodegeneration. FEBS J., 2007, 274, 1637-1650. Peterson, S.; Klabunde, T.; Lashuel, H.; Purkey, H.; Sacchettini, J.C.; Kelly, J.W. Inhibiting transthyretin conformational changes


[127] [128]



that lead to amyloid fibril formation. Proc. Natl. Acad. Sci. USA, 1998, 95, 12956-12960. Connelly, S.; Choi, S.; Johnson, S.M.; Kelly, J.W.; Wilson, I.A. Structure-based design of kinetic stabilizers that ameliorate the transthyretin amyloidoses. Curr. Opin. Struct. Biol., 2010, 20, 5462. Golde, T.E. Alzheimer disease therapy: Can the amyloid cascade be halted? J. Clin. Invest., 2003, 111, 11-18. Roberds, S.L.; Anderson, J.; Basi, G.; Bienkowski, M.J.; Branstetter, D.G.; Chen, K.S.; Freedman, S.B.; Frigon, N.L.; Games, D.; Hu, K.; Johnson-Wood, K.; Kappenman, K.E.; Kawabe, T.T.; Kola, I.; Kuehn, R.; Lee, M.; Liu, W.; Motter, R.; Nichols, N.F.; Power, M.; Robertson, D.W.; Schenk, D.; Schoor, M.; Shopp, G.M.; Shuck, M.E.; Sinha, S.; Svensson, K.; Tatsuno, G.; Tintrup, H.; Wijsman, J.; Wright, S.; McConlogue, L. BACE knockout mice are healthy despite lacking the primary betasecretase activity in brain: Implications for Alzheimer’s disease therapeutics. Hum. Mol. Genet., 2001, 10, 1317-1324. Grüninger-Leitch, F.; Schlatter, D.; Küng, E.; Nelböck, P.; Döbeli, H. Substrate and inhibitor profile of BACE (β-Secretase) and comparison with other mammalian aspartic proteases. J. Biol. Chem., 2002, 277, 4687-4693. Hong, L.; Koelsch, G.; Lin, X.; Wu, S.; Terzyan, S.; Ghosh, K.; Zhang, X.C.; Tang, J. Structure of the protease domain of memapsin 2 (Beta-Secretase) complexed with inhibitor. Science, 2000, 290, 150-153. Wolfe, M.S.; Esler, W.P.; Das, C. Continuing strategies for inhibiting Alzheimer’s γ-secretase. J. Mol. Neurosci., 2002, 19, 8387. Phiel, C.J.; Wilson, C.; Lee, V.M.-Y.; Klein, P.S. GSK-3alpha regulates production of Alzheimer’s disease amyloid-beta peptides. Nature, 2003, 423, 435-439. Janus, C.; Pearson, J.; McLaurin, J.; Mathews, P.M.; Jiang, Y.; Schmidt, S.D.; Chishti, M.; Horne, P.; Heslin, D.; French, J.; Mount, H.T.; Nixon, R.; Mercken, M.; Bergeron, C.; Fraser, P.E.; St George-Hyslop, P.; Westaway, D. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature, 2000, 408, 979-982. Morgan, D.; Diamond, D.M.; Gottschall, P.E.; Ugen, K.E.; Dickey, C.; Hardy, J.; Duff, K.; Jantzen, P.; DiCarlo, G.; Wilcock, D.; Connor, K.; Hatcher, J.; Hope, C.; Gordon, M.; Arendash, G.W. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature, 2000, 408, 982-985. Schenk, D.; Barbour, R.; Dunn, W.; Gordon, G.; Grajeda, H.; Guido, T.; Hu, K.; Huang, J.; Johnson-Wood, K.; Khan, K.; Kholodenko, D.; Lee, M.; Liao, Z.; Lieberburg, I.; Motter, R.; Mutter, L.; Soriano, F.; Shopp, G.; Vasquez, N.; Vandevert, C.; Walker, S.; Wogulis, M.; Yednock, T.; Games, D.; Seubert, P. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature, 1999, 400, 173-177. Pul, R.; Dodel, R.; Stangel, M. Antibody-based therapy in Alzheimer’s disease. Expert Opin. Biol. Ther., 2011, 11, 343-357. Schenk, D.; Hagen, M.; Seubert, P. Hopes remain for an Alzheimer’s vaccine. Current progress in beta-amyloid immunotherapy. Curr. Opin. Immunol., 2004, 16, 599-606. Bard, F.; Barbour, R.; Cannon, C.; Carretto, R.; Fox, M.; Games, D.; Guido, T.; Hoenow, K.; Hu, K.; Johnson-Wood, K.; Khan, K.; Kholodenko, D.; Lee, C.; Lee, M.; Motter, R.; Nguyen, M.; Reed, A.; Schenk, D.; Tang, P.; Vasquez, N.; Seubert, P.; Yednock, T. Epitope and isotype specificities of antibodies to beta -amyloid peptide for protection against Alzheimer’s disease-like neuropathology. Proc. Natl. Acad. Sci. USA, 2003, 100, 2023-2028. Fu, H.J.; Liu, B.; Frost, J.L.; Lemere, C.A. Amyloid-beta immunotherapy for Alzheimer’s disease. CNS Neurol. Disord. Drug Targets, 2010, 9, 197-206. Weggen, S.; Eriksen, J.L.; Das, P.; Sagi, S.; Wang, R.; Pietrzik, C.U.; Findlay, K.; Smith, T.E.; Murphy, M.P.; Bulter, T.; Kang, D.E.; Marquez-Sterling, N.; Golde, T.E.; Koo, E.H. A subset of NSAIDs lower amyloidogenic abeta42 independently of cyclooxygenase activity. Nature, 2001, 414, 212-216. Eriksen, J.L.; Sagi, S.A.; Smith, T.E.; Weggen, S.; Das, P.; McLendon, D.C.; Ozols, V.V.; Jessing, K.W.; Zavitz, K.H.; Koo, E.H.; Golde, T.E. NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower abeta 42 in vivo. J. Clin. Invest., 2003, 112, 440-449.

Pe N rs ot on fo al rD U is se tri O bu n tio ly n


Fatima et al.












Emerging Targets and Latest Proteomics Based Therapeutic



[145] [146]

[147] [148]











Puglielli, L.; Tanzi, R.E.; Kovacs, D.M. Alzheimer’s disease: The cholesterol connection. Nat. Neurosci., 2003, 6, 345-351. Shepherd, J.; Blauw, G.J.; Murphy, M.B.; Bollen, E.L.E.M.; Buckley, B.M.; Cobbe, S.M.; Ford, I.; Gaw, A.; Hyland, M.; Jukema, J.W.; Kamper, A.M.; Macfarlane, P.W.; Meinders, A.E.; Norrie, J.; Packard, C.J.; Perry, I.J.; Stott, D.J.; Sweeney, B.J.; Twomey, C.; Westendorp, R.G.J. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): A randomised controlled trial. Lancet, 2002, 360, 1623-1630. Poirier, M.A.; Li, H.; Macosko, J.; Cai, S.; Amzel, M.; Ross, C.A. Huntingtin spheroids and protofibrils as precursors in polyglutamine fibrilization. J. Biol. Chem., 2002, 277, 4103241037. Sánchez, I.; Mahlke, C.; Yuan, J. Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature, 2003, 421, 373-379. Heiser, V.; Scherzinger, E.; Boeddrich, A.; Nordhoff, E.; Lurz, R.; Schugardt, N.; Lehrach, H.; Wanker, E.E. Inhibition of huntingtin fibrillogenesis by specific antibodies and small molecules: Implications for huntington’s disease therapy. Proc. Natl. Acad. Sci. USA, 2000, 97, 6739-6744. Medina, D.X.; Caccamo, A.; Oddo, S. Methylene blue reduces aβ levels and rescues early cognitive deficit by increasing proteasome activity. Brain Pathol., 2011, 21, 140-149. Wischik, C.M.; Edwards, P.C.; Lai, R.Y.; Roth, M.; Harrington, C.R. Selective inhibition of Alzheimer disease-like Tau aggregation by phenothiazines. Proc. Natl. Acad. Sci. USA, 1996, 93, 11213-11218. Hochgräfe, K.; Sydow, A.; Matenia, D.; Cadinu, D.; Könen, S.; Petrova, O.; Pickhardt, M.; Goll, P.; Morellini, F.; Mandelkow, E.; Mandelkow, E.-M. Preventive methylene blue treatment preserves cognition in mice expressing full-length pro-aggregant human Tau. Acta Neuropathol. Commun., 2015, 3, 25. Bulic, B.; Pickhardt, M.; Schmidt, B.; Mandelkow, E.M.; Waldmann, H.; Mandelkow, E. Development of Tau aggregation inhibitors for Alzheimer’s disease. Angewandte Chemie, 2009, 48, 1740-1752. Gregor Larbig, B.S.P.; Marcus Pickhardt, B.S.P.; David G. Lloyd, B.S.P.; Boris Schmidt, B.S.P.; Eckhard Mandelkow, B.S.P. Screening for inhibitors of Tau protein aggregation into Alzheimer paired helical filaments: A ligand based approach results in successful scaffold hopping. Curr. Alzheimer Res., 2007, 4, 315323. McLaurin, J.; Franklin, T.; Chakrabartty, A.; Fraser, P.E. Phosphatidylinositol and inositol involvement in Alzheimer amyloid-beta fibril growth and arrest. J. Mol. Biol., 1998, 278, 183194. McLaurin, J.; Golomb, R.; Jurewicz, A.; Antel, J.P.; Fraser, P.E. Inositol stereoisomers stabilize an oligomeric aggregate of Alzheimer amyloid  beta peptide and inhibit abeta -induced toxicity. J. Biol. Chem., 2000, 275, 18495-18502. Hawkes, C.A.; Deng, L.H.; Shaw, J.E.; Nitz, M.; McLaurin, J. Small molecule  beta-amyloid inhibitors that stabilize protofibrillar structures in vitro improve cognition and pathology in a mouse model of Alzheimer’s disease. Eur. J. Neurosci., 2010, 31, 203-213. Pitt, J.; Thorner, M.; Brautigan, D.; Larner, J.; Klein, W.L. Protection against the synaptic targeting and toxicity of Alzheimer’s-associated aβ oligomers by insulin mimetic chiroinositols. FASEB J., 2013, 27, 199-207. Heiser, V.; Engemann, S.; Bröcker, W.; Dunkel, I.; Boeddrich, A.; Waelter, S.; Nordhoff, E.; Lurz, R.; Schugardt, N.; Rautenberg, S.; Herhaus, C.; Barnickel, G.; Böttcher, H.; Lehrach, H.; Wanker, E.E. Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington’s disease by using an automated filter retardation assay. Proc. Natl. Acad. Sci. USA, 2002, 99(Suppl 4), 16400-16406. Hockly, E.; Tse, J.; Barker, A.L.; Moolman, D.L.; Beunard, J.L.; Revington, A.P.; Holt, K.; Sunshine, S.; Moffitt, H.; Sathasivam, K.; Woodman, B.; Wanker, E.E.; Lowden, P.A.S.; Bates, G.P. Evaluation of the benzothiazole aggregation inhibitors riluzole and PGL-135 as therapeutics for Huntington’s disease. Neurobiol. Dis., 2006, 21, 228-236. Ehrnhoefer, D.E.; Duennwald, M.; Markovic, P.; Wacker, J.L.; Engemann, S.; Roark, M.; Legleiter, J.; Marsh, J.L.; Thompson, L.M.; Lindquist, S.; Muchowski, P.J.; Wanker, E.E. Green tea (-)-




[162] [163]



[166] [167]











epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington’s disease models. Hum. Mol. Genet., 2006, 15, 2743-2751. Bieschke, J.; Russ, J.; Friedrich, R.P.; Ehrnhoefer, D.E.; Wobst, H.; Neugebauer, K.; Wanker, E.E. EGCG remodels mature alphasynuclein and amyloid-beta fibrils and reduces cellular toxicity. Proc. Natl. Acad. Sci. USA, 2010, 107, 7710-7715. Hauber, I.; Hohenberg, H.; Holstermann, B.; Hunstein, W.; Hauber, J. The main green tea polyphenol epigallocatechin-3-gallate counteracts semen-mediated enhancement of HIV infection. Proc. Natl. Acad. Sci. USA, 2009, 106, 9033-9038. Hudson, S.A.; Ecroyd, H.; Dehle, F.C.; Musgrave, I.F.; Carver, J.A. (-)-Epigallocatechin-3-Gallate (EGCG) maintains κ -casein in its pre-fibrillar state without redirecting its aggregation pathway. J. Mol. Biol., 2009, 392, 689-700. Bhullar, K.S.; Rupasinghe, H.P.V. Polyphenols: Multipotent therapeutic agents in neurodegenerative diseases. Oxid. Med. Cell. Longev., 2013, 2013, 891748. Mähler, A.; Mandel, S.; Lorenz, M.; Ruegg, U.; Wanker, E.E.; Boschmann, M.; Paul, F. Epigallocatechin-3-gallate: A useful, effective and safe clinical approach for targeted prevention and individualised treatment of neurological diseases? EPMA J., 2013, 4, 5. Mason, J.M.; Kokkoni, N.; Stott, K.; Doig, A.J. Design strategies for anti-amyloid agents. Curr. Opin. Struct. Biol., 2003, 13, 526532. Salomon, A.R.; Marcinowski, K.J.; Friedland, R.P.; Zagorski, M.G. Nicotine inhibits amyloid formation by the  beta-peptide. Biochemistry, 1996, 35, 13568-13578. Camilleri, P.; Haskins, N.J.; Howlett, D.R. B-cyclodextrin interacts with the Alzheimer amyloid B-A4 peptide. FEBS Lett., 1994, 341, 256-258. Howlett, D.; Cutler, P.; Heales, S.; Camilleri, P. Hemin and related porphyrins inhibit  beta-amyloid aggregation. FEBS Lett., 1997, 417, 249-251. Wasilewska-Sampaio, A.P.; Silveira, M.S.; Holub, O.; Goecking, R.; Gomes, F.C.; Neto, V.M.; Linden, R.; Ferreira, S.T.; De Felice, F.G. Neuritogenesis and neuronal differentiation promoted by 2,4dinitrophenol, a novel anti-amyloidogenic compound. FASEB J., 2005, 19, 1627-1636. De Felice, F.G.; Vieira, M.N.N.; Saraiva, L.M.; Figueroa-Villar, J.D.; Garcia-Abreu, J.; Liu, R.; Chang, L.; Klein, W.L.; Ferreira, S.T. Targeting the neurotoxic species in Alzheimer’s disease: Inhibitors of abeta oligomerization. FASEB J., 2004, 18, 13661372. Merlini, G.; Ascari, E.; Amboldi, N.; Bellotti, V.; Arbustini, E.; Perfetti, V.; Ferrari, M.; Zorzoli, I.; Marinone, M.G.; Garini, P. Interaction of the anthracycline 4’-iodo-4'-deoxydoxorubicin with amyloid fibrils: Inhibition of amyloidogenesis. Proc. Natl. Acad. Sci. USA, 1995, 92, 2959-2963. Wood, S.J.; Mackenzie, L.; Maleeff, B.; Hurle, M.R.; Wetzel, R. Selective inhibition of Ab fibril formation. J. Biol. Chem., 1996, 271, 4086-4092. Tiwari, S.K.; Agarwal, S.; Seth, B.; Yadav, A.; Nair, S.; Bhatnagar, P.; Karmakar, M.; Kumari, M.; Chauhan, L.K.S.; Patel, D.K.; Srivastava, V.; Singh, D.; Gupta, S.K.; Tripathi, A.; Chaturvedi, R.K.; Gupta, K.C. Curcumin-loaded nanoparticles potently induce adult neurogenesis and reverse cognitive deficits in Alzheimer’s disease model via canonical wnt/ β-catenin pathway. ACS Nano, 2014, 8, 76-103. Taniguchi, S.; Suzuki, N.; Masuda, M.; Hisanaga, S.I.; Iwatsubo, T.; Goedert, M.; Hasegawa, M. Inhibition of heparin-induced tau filament formation by phenothiazines, polyphenols, and porphyrins. J. Biol. Chem., 2005, 280, 7614-7623. Wang, J.; Gines, S.; MacDonald, M.E.; Gusella, J.F. Reversal of a full-length mutant huntingtin neuronal cell phenotype by chemical inhibitors of polyglutamine-mediated aggregation. BMC Neurosci., 2005, 6, 1. Netland, E.E.; Newton, J.L.; Majocha, R.E.; Tate, B.A. Indomethacin reverses the microglial response to amyloid  betaprotein. Neurobiol. Aging, 1998, 19, 201-204. Pappolla, M.; Bozner, P.; Soto, C.; Shao, H.; Robakis, N.K.; Zagorski, M.; Frangione, B.; Ghiso, J. Inhibition of Alzheimer beta-fibrillogenesis by melatonin. J. Biol. Chem., 1998, 273, 71857188.

Pe N rs ot on fo al rD U is se tri O bu n tio ly n


Current Protein and Peptide Science, 2018, Vol. 19, No. 9

874 Current Protein and Peptide Science, 2018, Vol. 19, No. 9




[181] [182]

[183] [184]

[185] [186]


[188] [189]




[193] [194]

[195] [196]


Tomiyama, T.; Shoji, A.; Kataoka, K.I.; Suwa, Y.; Asano, S.; Kaneko, H.; Endo, N. Inhibition of amyloid β protein aggregation and neurotoxicity by rifampicin: Its possible function as a hydroxyl radical scavenger. J. Biol. Chem., 1996, 271, 6839-6844. Umeda, T.; Ono, K.; Sakai, A.; Yamashita, M.; Mizuguchi, M.; Klein, W.L.; Yamada, M.; Mori, H.; Tomiyama, T. Rifampicin is a candidate preventive medicine against amyloid β and Tau oligomers. Brain, 2016, 139, 1568-1586. Lendel, C.; Bertoncini, C.W.; Cremades, N.; Waudby, C.A.; Vendruscolo, M.; Dobson, C.M.; Schenk, D.; Christodoulou, J.; Toth, G. On the mechanism of nonspecific inhibitors of protein aggregation: Dissecting the interactions of α-synuclein with congo red and lacmoid. Biochemistry, 2009, 48, 8322-8334. Abelein, A.; Bolognesi, B.; Dobson, C.M.; Gräslund, A.; Lendel, C. Hydrophobicity and conformational change as mechanistic determinants for nonspecific modulators of amyloid β selfassembly. Biochemistry, 2012, 51, 126-137. Lendel, C.; Bolognesi, B.; Wahlström, A.; Dobson, C.M.; Gräslund, A. Detergent-like Interaction of congo red with the amyloid β peptide. Biochemistry, 2010, 49, 1358-1360. Ryan, T.M.; Griffin, M.D.W.; Teoh, C.L.; Ooi, J.; Howlett, G.J. High-affinity amphipathic modulators of amyloid fibril nucleation and elongation. J. Mol. Biol., 2011, 406, 416-429. Meng, X.; Munishkina, L.A.; Fink, A.L.; Uversky, V.N. Molecular mechanisms underlying the flavonoid-induced inhibition of alphasynuclein fibrillation. Biochemistry, 2009, 48, 8206-8224. Meng, X.; Munishkina, L.A.; Fink, A.L.; Uversky, V.N. Effects of various flavonoids on the α -synuclein fibrillation process. Parkinsons. Dis., 2010, 2010, 650794. Ali, Y.O.; Kitay, B.M.; Zhai, R.G. Dealing with misfolded proteins: Examining the neuroprotective role of molecular chaperones in neurodegeneration. Molecules, 2010, 15, 6859-6887. McLean, P.J.; Kawamata, H.; Shariff, S.; Hewett, J.; Sharma, N.; Ueda, K.; Breakefield, X.O.; Hyman, B.T. TorsinA and heat shock proteins act as molecular chaperones: suppression of alphasynuclein aggregation. J. Neurochem., 2002, 83, 846-854. Dedmon, M.M.; Christodoulou, J.; Wilson, M.R.; Dobson, C.M. Heat shock protein 70 inhibits alpha-synuclein fibril formation via preferential binding to prefibrillar species. J. Biol. Chem., 2005, 280, 14733-14740. Le, W.; Appel, S.H. Mutant genes responsible for Parkinson’s disease. Curr. Opin. Pharmacol., 2004, 4, 79-84. Li, H.M.; Niki, T.; Taira, T.; Iguchi-Ariga, S.M.M.; Ariga, H. Association of DJ-1 with chaperones and enhanced association and colocalization with mitochondrial hsp70 by oxidative stress. Free Radic. Res., 2005, 39, 1091-1099. Meriin, B.; Sherman, M.Y. Role of molecular chaperones in neurodegenerative disorders. Int. J. Hyperthermia, 2005, 21, 403419. Tsai, Y.C.; Fishman, P.S.; Thakor, N. V.; Oyler, G.A. Parkin facilitates the elimination of expanded polyglutamine proteins and leads to preservation of proteasome function. J. Biol. Chem., 2003, 278, 22044-22055. Rankawek, K.; Bosman, G.J.C.; De Jong, W.W. Expression of small heat-shock protein hsp 27 in reactive gliosis in Alzheimer disease and other types of dementia. Acta Neuropathol., 1994, 87, 511-519. Yoo, B.C.; Seidl, R.; Cairns, N.; Lubec, G. Heat-shock protein 70 levels in brain of patients with down syndrome and alzheimer’s Disease. J. Neural Transm. Suppl., 1999, 57, 315-322. Yang, Y.; Turner, R.S.; Gaut, J.R. The chaperone BiP/GRP78 binds to amyloid precursor protein and decreases Abeta40 and Abeta42 secretion. J. Biol. Chem., 1998, 273, 25552-25555. Evans, C.G.; Wisén, S.; Gestwicki, J.E. Heat shock proteins 70 and 90 inhibit early stages of amyloid β-(1-42) aggregation in vitro. J. Biol. Chem., 2006, 281, 33182-33191. Wilhelmus, M.M.M.; Otte-Höller, I.; Wesseling, P.; De Waal, R.M.W.; Boelens, W.C.; Verbeek, M.M. Specific association of small heat shock proteins with the pathological hallmarks of Alzheimer’s disease brains. Neuropathol. Appl. Neurobiol., 2006, 32, 119-130. Fonte, V.; Kipp, D.R.; Yerg, J.; Merin, D.; Forrestal, M.; Wagner, E.; Roberts, C.M.; Link, C.D. Suppression of in vivo  beta-amyloid peptide toxicity by overexpression of the Hsp-16.2 small chaperone protein. J. Biol. Chem., 2008, 283, 784-791.






Petrucelli, L.; Dickson, D.; Kehoe, K.; Taylor, J.; Snyder, H.; Grover, A.; De Lucia, M.; McGowan, E.; Lewis, J.; Prihar, G.; Kim, J.; Dillmann, W.H.; Browne, S.E.; Hall, A.; Voellmy, R.; Tsuboi, Y.; Dawson, T.M.; Wolozin, B.; Hardy, J.; Hutton, M. CHIP and Hsp70 regulate Tau ubiquitination, degradation and aggregation. Hum. Mol. Genet., 2004, 13, 703-714. Shimura, H.; Miura-Shimura, Y.; Kosik, K.S. Binding of Tau to heat shock protein 27 leads to decreased concentration of hyperphosphorylated tau and enhanced cell survival. J. Biol. Chem., 2004, 279, 17957-17962. Jana, N.R.; Tanaka, M.; Wang, G.H.; Nukina, N. Polyglutamine length-dependent interaction of Hsp40 and Hsp70 family chaperones with truncated N-terminal huntingtin: Their role in suppression of aggregation and cellular toxicity. Hum. Mol. Genet., 2000, 9, 2009-2018. Wyttenbach, A.; Sauvageot, O.; Carmichael, J.; Diaz-Latoud, C.; Arrigo, A.-P.; Rubinsztein, D.C. Heat shock protein 27 prevents cellular polyglutamine toxicity and suppresses the increase of reactive oxygen species caused by huntingtin. Hum. Mol. Genet., 2002, 11, 1137-1151. Muchowski, P.J.; Schaffar, G.; Sittler, A.; Wanker, E.E.; HayerHartl, M.K.; Hartl, F.U. Hsp70 and hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils. Proc. Natl. Acad. Sci. USA, 2000, 97, 7841-7846. Warrick, J.M.; Paulson, H.L.; Gray-Board, G.L.; Bui, Q.T.; Fischbeck, K.H.; Pittman, R.N.; Bonini, N.M. Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in drosophila. Cell, 1998, 93, 939-949. Cummings, C.J.; Sun, Y.; Opal, P.; Antalffy, B.; Mestril, R.; Orr, H.T.; Dillmann, W.H.; Zoghbi, H.Y. Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Hum. Mol. Genet., 2001, 10, 1511-1518. Loo, T.; Clarke, D. Chemical and pharmacological chaperones as new therapeutic agents. Expert Rev. Mol. Med., 2007, 9, 1-18. Arakawa, T.; Ejima, D.; Kita, Y.; Tsumoto, K. Small molecule pharmacological chaperones: From thermodynamic stabilization to pharmaceutical drugs. Biochim. Biophys. Acta, 2006, 1764, 16771687. Papp, E.; Csermely, P. Chemical chaperones: Mechanisms of action and potential use. Handb. Exp. Pharmacol., 2006, 172, 405416. Sato, S.; Ward, C.L.; Krouse, M.E.; Wine, J.J.; Kopito, R.R. Glycerol reverses the misfolding phenotype of the most common cystic fibrosis mutation. J. Biol. Chem., 1996, 271, 635-638. Burrows, J.; Willis, L.K.; Perlmutter, D.H. Chemical chaperones mediate increased secretion of mutant Alpha 1-Antitrypsin (Alpha 1-AT) Z: A potential pharmacological strategy for prevention of liver injury and emphysema in Alpha 1-AT deficiency. Proc. Natl. Acad. Sci. USA, 2000, 97, 1796-1801. Tamarappoo, B.K.; Verkman, A.S. Defective aquaporin-2 trafficking in nephrogenic diabetes insipidus and correction by chemical chaperones. J. Clin. Invest., 1998, 101, 2257-2267. Tan, C.M.; Highfield Nickols, H.; Limbird, L.E. Appropriate polarization following pharmacological rescue of V2 vasopressin receptors encoded by X-linked nephrogenic diabetes insipidus alleles involves a conformation of the receptor that also attains mature glycosylation. J. Biol. Chem., 2003, 278, 35678-35686. Fan, J.Q.; Ishii, S.; Asano, N.; Suzuki, Y. Accelerated transport and maturation of lysosomal alpha-galactosidase A in fabry lymphoblasts by an enzyme inhibitor. Nat. Med., 1999, 5, 112-115. Foster, B.A.; Coffey, H.A.; Morin, M.J.; Rastinejad, F.; Hollstein, M.; Rosenfeld, M.R.; Nielsen, L.L.; Kern, S.E.; Milner, J.; Watson, J. V.; Halazonetis, T.D.; Davis, L.J.; Kandil, A.N.; Cho, Y.; Gorina, S.; Jeffrey, P.D.; Pavletich, N.P.; Bullock, N.; Friedlander, P.; Legros, Y.; Soussi, T.; Prives, C.; Gamble, J.; Milner, J.; Wang, E.H.; Friedman, P.N.; Prives, C.; Hainaut, P.; Milner, J.; Legros, Y.; Daniels, D.A.; Lane, D.P.; Bartek, J.; Iggo, R.; Gannon, J.; Lane, D.P.; Stephen, C.W.; Lane, D.P.; Hupp, T.R.; Sparks, A.; Lane, D.P.; Selivanova, G.; Pavletich, N.P.; Chambers, K.A.; Pabo, C.O.; Chen, J.Y.; Funk, W.D.; Wright, W.E.; Shay, J.W.; Minna, J.D.; Prusiner, S.B.; Taubes, G.; Miroy, G.J.; Sato, S.; Ward, C.L.; Krause, M.E.; Wine, J.J.; Kopito, R.R.; Euhus, D.M.; Hudd, C.; LaRegina, M.C.; Johnson, F.E. Pharmacological rescue of mutant p53 conformation and function. Science, 1999, 286, 2507-2510.

Pe N rs ot on fo al rD U is se tri O bu n tio ly n


Fatima et al.



[205] [206]


[208] [209]



[212] [213]

Emerging Targets and Latest Proteomics Based Therapeutic










[224] [225]

Loo, T.W.; Clarke, D.M. Correction of defective protein kinesis of human P-glycoprotein mutants by substrates and modulators. J. Biol. Chem., 1997, 272, 709-712. Brown, C.R.; Hong-Brown, L.Q.; Biwersi, J.; Verkman, A.S.; Welch, W.J. Chemical chaperones correct the mutant phenotype of the delta F508 cystic fibrosis transmembrane conductance regulator protein. Cell Stress Chaperones, 1996, 1, 117-125. Loo, T.W.; Bartlett, M.C.; Wang, Y.; Clarke, D.M. The chemical chaperone CFcor-325 repairs folding defects in the transmembrane domains of CFTR-processing mutants. Biochem. J., 2006, 395, 537-542. Gordon, D.J.; Sciarretta, K.L.; Meredith, S.C. Inhibition of  betaamyloid(40) fibrillogenesis and disassembly of  beta-amyloid(40) fibrils by short  beta-amyloid congeners containing N-methyl amino acids at alternate residues. Biochemistry, 2001, 40, 82378245. Gordon, D.J.; Meredith, S.C. Probing the role of backbone hydrogen bonding in  beta-amyloid fibrils with inhibitor peptides containing ester bonds at alternate positions. Biochemistry, 2003, 42, 475-485. Rzepecki, P.; Nagel-Steger, L.; Feuerstein, S.; Linne, U.; Molt, O.; Zadmard, R.; Aschermann, K.; Wehner, M.; Schrader, T.; Riesner, D. Prevention of Alzheimer’s disease-associated Abeta aggregation by rationally designed nonpeptidic  beta-sheet ligands. J. Biol. Chem., 2004, 279, 47497-47505. Morris, M.C.; Evans, D.; Bienias, J.L.; Tangney, C.C.; Bennett, D.; Aggarwal, N.; Wilson, R.S.; Scherr, P. Dietary intake of antioxidant nutrients and the risk of incident alzheimer disease in a biracial community study. JAMA, 2002, 287, 3230-3237. de Rijk, M.C.; Breteler, M.M.; den Breeijen, J.H.; Launer, L.J.; Grobbee, D.E.; van der Meche, F.G.; Hofman, A. Dietary antioxidants and Parkinson disease. The Rotterdam Study. Arch. Neurol., 1997, 54, 762-765. Lemeshow, S.; Letenneur, L.; Dartigues, J.-F.; Lafont, S.; Orgogozo, J.-M.; Commenges, D. Illustration of analysis taking into account complex survey considerations: The association between wine consumption and dementia in the PAQUID study. Am. J. Epidemiol., 1998, 148, 298-306. Oken, B.S.; Storzbach, D.M.; Kaye, J.A. The Efficacy of ginkgo biloba on cognitive function in Alzheimer disease. Arch. Neurol., 1998, 55, 1409-1415. Qi, H.; Li, S. Dose-response meta-analysis on coffee, tea and caffeine consumption with risk of Parkinson’s disease. Geriatr. Gerontol. Int., 2014, 14, 430-439. Jurado-Coronel, J.C.; Ávila-Rodriguez, M.; Echeverria, V.; Hidalgo, O.A.; Gonzalez, J.; Aliev, G.; Barreto, G.E. Implication of green tea as a possible therapeutic approach for Parkinson disease. CNS Neurol. Disord. Drug Targets, 2016, 15, 292-300.


[227] [228]




[232] [233]






Commenges, D.; Scotet, V.; Renaud, S.; Jacqmin-Gadda, H.; Barberger-Gateau, P.; Dartigues, J.F. Intake of flavonoids and risk of dementia. Eur. J. Epidemiol., 2000, 16, 357-363. Putics, A.; Végh, E.M.; Csermely, P.; Soti, C. Resveratrol induces the heat-shock response and protects human cells from severe heat stress. Antioxid. Redox Signal., 2008, 10, 65-75. Lim, G.P.; Chu, T.; Yang, F.; Beech, W.; Frautschy, S.; Cole, G.M. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J. Neurosci., 2001, 21, 8370-8377. in t’ Veld, B.A.; Ruitenberg, A.; Hofman, A.; Launer, L.J.; van Duijn, C.M.; Stijnen, T.; Breteler, M.M.; Stricker, B.H. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N. Engl. J. Med., 2001, 345, 1515-1521. Kim, W.; Kim, Y.; Min, J.; Kim, D.J.; Chang, Y.T.; Hecht, M.H. A high-throughput screen for compounds that inhibit aggregation of the Alzheimer’s peptide. ACS Chem. Biol., 2006, 1, 461-469. Chen, J.; Armstrong, A.H.; Koehler, A.N.; Hecht, M.H. Small molecule microarrays enable the discovery of compounds that bind the Alzheimer’s Aβ peptide and reduce its cytotoxicity. J. Am. Chem. Soc., 2010, 132, 17015-17022. Landau, M.; Sawaya, M.R.; Faull, K.F.; Laganowsky, A.; Jiang, L.; Sievers, S.A.; Liu, J.; Barrio, J.R.; Eisenberg, D. Towards a pharmacophore for amyloid. PLoS Biol., 2011, 9, e1001080. Herrera, F.E.; Chesi, A.; Paleologou, K.E.; Schmid, A.; Munoz, A.; Vendruscolo, M.; Gustincich, S.; Lashuel, H.A.; Carloni, P. Inhibition of α-synuclein fibrillization by dopamine is mediated by interactions with five C-terminal residues and with E83 in the NAC region. PLoS One, 2008, 3. Simonsen, A.H.; Hansson, S.F.; Ruetschi, U.; McGuire, J.; Podust, V.N.; Davies, H.A.; Mehta, P.; Waldemar, G.; Zetterberg, H.; Andreasen, N.; Wallin, A.; Blennow, K. Amyloid β1-40 quantification in CSF: Comparison between chromatographic and immunochemical methods. Dement. Geriatr. Cogn. Disord., 2007, 23, 246-250. Acquadro, E.; Caron, I.; Tortarolo, M.; Bucci, E.M.; Bendotti, C.; Corpillo, D. Human SOD1-G93A specific distribution evidenced in murine brain of a transgenic model for amyotrophic lateral sclerosis by MALDI imaging mass spectrometry. J. Proteome Res., 2014, 13, 1800-1809. Agresta, A.M.; De Palma, A.; Bardoni, A.; Salvini, R.; Iadarola, P.; Mauri, P.L. Proteomics as an innovative tool to investigate frontotemporal disorders. Proteomics, 2016, 10, 457-469. Velez, G.; Roybal, C.; Colgan, D.; Tsang, S.H.; Bassuk, A.G.; Mahajan, V.B. Precision medicine: Personalized proteomics for the diagnosis and treatment of idiopathic inflammatory disease. JAMA Ophthalmol., 2016, 134(4), 444-448.

Pe N rs ot on fo al rD U is se tri O bu n tio ly n


Current Protein and Peptide Science, 2018, Vol. 19, No. 9