Protein Misfolding and Aggregation in Neurodegenerative Disorders: Focus on Chaperone-Mediated Protein Folding Machinery


Kritika Raj, Soram Idiyasan Chanu, Surajit Sarkar


Kritika Raj, Soram Idiyasan Chanu, Surajit Sarkar, Department of Genetics, University of Delhi South Campus, Benito Juarez Road, New Delhi-110 021, India

Correspondence to: Surajit Sarkar, Department of Genetics, University of Delhi South Campus, Benito Juarez Road, New Delhi-110 021, India


Telephone: +91-11-24112761

Received: December 22, 2014            Revised: March 3, 2015

Accepted: March 9, 2015

Published online: May 13, 2015



Proteins are structurally complex biomolecules which regulate fundamental processes of the cellular systems. An integrated network of molecular chaperones, ubiquitin proteasome system and autophagy regulate the cellular protein quality and maintain the balance between folded and unfolded proteins. However, several chronic challenges such as aging related physiological changes, diseases and certain stress conditions interfere with protein functioning. This leads to formation and accumulation of potentially toxic proteinaceous species in the cellular system. It is increasingly clear now that impairment(s) of protein quality control system is one of the common mechanisms, which leads to onset and progression of various human diseases including neurodegenerative disorders. Occurrence of cellular fibrillar protein aggregates marks the signature feature shared by most of these disorders. Molecular chaperones are the key regulators of the protein quality control machinery which have been identified as modulators of neurodegenerative diseases. They have been found to play essential role in eliminating toxic proteins by either inhibiting or promoting the process of aggregate formation. This review focuses on elucidating the role of chaperone-mediated protein folding and its application as a promising choice for development of novel therapeutic strategies against neurodegenerative disorders.

© 2015 ACT. All rights reserved.


Key words: Neurodegenerative disorders; Molecular chaperones; Protein folding


Raj K, Chanu SI, Sarkar S. Protein Misfolding and Aggregation in Neurodegenerative Disorders: Focus on Chaperone-Mediated Protein Folding Machinery. International Journal of Neurology Research 2015; 1(2): 72-78 Available from: URL:



Proteins are delicate, versatile and structurally complex biomolecules which regulate fundamental processes of the cellular systems. They are synthesized as long stretches of amino acid chains and in order to achieve the functional state each polypeptide chain must be folded into a unique 3-dimensional structure[1]. However, proteins have a very narrow range of thermodynamically stable physiological environment inside the cells to achieve correct folding and to function[2]. In addition, several chronic challenges such as aging related physiological changes, diseases and certain stress conditions also interfere with protein functioning[2]. Therefore, how the cells manage their proteome and ensure their metastable conformations to retain the conformational flexibility in the ever changing cellular environment has emerged as a fundamental question in contemporary biomedical research.

    Cellular system has developed a specialized folding machinery which has been optimised to function in co-operation with ribosome dependent protein synthesis system[3]. However, it has been estimated that only a fraction of the newly synthesized protein accomplish the functional folded state and others do not attain the ordered 3-dimensional structure, but have the potential to adopt folding conformation only after interaction with some folding substrates[4]. In a crowding environment where the cytosolic protein concentration reaches upto ~300-400 gram/litre (gl-1), the folding becomes more challenging and the proteins are at great risk to adopt aberrant folding and aggregation[5]. This leads to formation and accumulation of potentially toxic proteinaceous species in the cellular system[6]. Therefore, cells have to routinely cope up with the problems of misfolded proteins owing to the rapidly changing cellular homeostasis associated with varying physiology and stressful conditions[7]. In view of the above, cellular system has developed a well-balanced protein quality control system to maintain proteome homeostasis which is essential for its normal functioning. An integrated network of molecular chaperones, ubiquitin proteasome system and autophagy system regulate the cellular protein quality and maintain the balance between folded and folding proteins[8]. Chaperones, in cooperation with their regulators assist de-novo or refolding of the nascent and denatured proteins respectively, along with selective removal of the irreversibly folded and aggregated proteins[9,10]. It has been well demonstrated that impairments of protein quality control system is one of the common mechanisms which leads to onset and progression of various human diseases including neurodegenerative disorders[11,12]. Present article has been divided in two sections: first section provides a brief overview of the chaperone based cellular protein folding and quality control machinery, and second part focuses on the impact of impaired folding machinery on onset and progression of neurodegenerative disorders. In addition, some recent findings on the ability of chaperones to suppress such fatal disorders have also been discussed.


Molecular chaperons in protein folding and quality control

Physiological and environmental stress such as aging, diseases, heat, heavy metal ions and UV exposure induce damages to cellular proteins and accelerate imbalances in the cellular proteome[13]. Molecular chaperones are protective proteins which assist efficient folding/re-folding of newly synthesized and denatured proteins, without being part of the final confirmation of the native protein[9]. Originally, chaperons were identified as proteins that were overexpressed in response to stress[14]. Later, functions of these proteins were also found to be essential to maintain the balance between de-novo folding and regulation of degradation pathways under normal physiological conditions. Nevertheless, despite of its constitutive levels, the expression and synthesis of these proteins greatly increases during the course of stress and therefore, these group of proteins are also known as heat shock proteins (Hsps)[7]. Classified according to the molecular weight and homologies, cells consist of several classes of chaperones such as Hsp40, Hsp60, Hsp70, Hsp90, Hsp100 and the small Hsps (sHsps)[15]. In the cellular system, three classes of chaperones - Hsp70, Hsp60 and Hsp90 - largely participate in de-novo folding and refolding of proteins in an ATP dependent manner[16].

    Chaperones start functioning from the point where stretches of nascent polypeptide chain get released from the polyribosomes[17]. Molecular chaperones recognize hydrophobic residues or unstructured peptide bonds exposed by non-native proteins. Such hydrophobic residues or unstructured peptide bonds are buried inside during native confirmation. Several chaperones such as trigger factors, ribosome binding Hsp70s, nascent chain associated complex (NAC), ribosome associated complex (RAC) etc. bind to the nascent proteins and assist co-translational folding[3]. However, co-translational folding is possible only for small and single domain proteins and majority of the cellular proteins are multi-domain and large. When such proteins are released in the cytoplasm, exposed non-native structures in the nascent proteins trigger self-aggregation[6]. Hsp70 along with several other molecular chaperones plays a central role in identification and stabilization of such newly synthesized unfolded proteins. Hsp70 is a ubiquitously expressed, stress inducible multifunctional chaperone which mediates a variety of biological processes, including folding, targeting, degradation and interactions of proteins[16]. Hsp70 consists of a N-terminal ATP-binding domain (NBD) and a substrate binding domain (SBD) near the C-terminal lid region[18]. Co-factors of Hsp70 include Hsp40/DnaJ family proteins and nucleotide exchange factor which assist cycles of substrate binding and release in an ATP dependent manner[19].

    Successive rounds of Hsp70 mediated folding results in the formation of fully folded substrates. However, generation of terminally misfolded or slowly folding species is also possible during this phenomenon. In view of above, selective degradation of misfolded protein is needed to avoid accumulation of potentially toxic aggregates. The folding pathway continues to correct the slowly folding or misfolded species for which Hsp70-substrate complex recruits Hsp90 and other chaperones. Hsp90 is a crucial regulator of protein homeostasis which also functions via an ATP-dependent hydrolytic cycle[16]. Hsp90 acts downstream of Hsp70 and assists in achieving conformational maturation of various signal transduction proteins including kinases and many of the steroid hormone receptors[16]. Similar to Hsp70, Hsp90 has several regulators and co-chaperons such as Hop, CDC37, AHA1, p23 etc. which assist in attaining correct folding and stability of their substrates[20]. Hop allows substrate transfer through its tetratricopeptide repeat (TPR) domain and acts as a direct link between Hsp70 and Hsp90[21]. Moreover, Hsp40/Hsp70 and Hsp90 have also been reported to be involved in regulating ubiquitin proteasome system and autophagy[16]. This implies the fact that chaperones also facilitate timely removal of misfolded proteins. Quality control of misfolded proteins generated by Hsp70 and Hsp90 folding machinery is found to be further regulated by a different TPR domain-containing co-chaperones such as C terminus domain of Hsc70 interacting protein (CHIP)[22]. CHIP associates with Hsp70 or Hsp90 through its TPR domain and ubiquitinates misfolded substrates and target them for endoplasmic-reticulum-associated protein degradation pathway[22]. Interestingly, many of the Hsp90 substrates also include oncogenic proteins like kinases and transcription factors, documenting its role in tumor development[23]. Therefore, inhibition of Hsp90 has emerged as a novel therapeutic approach in cancer treatment.

    As discussed earlier, protein folding in cytosol is generally achieved by Hsp70 along with downstream chaperones and chaperonins. Chaperonins are large multimember ring complexes that provide posttranslational folding of proteins in an isolated compartment, unimpaired by aggregation[24]. They promote folding of cytosolic proteins with size upto ~60 kDa; which are large, slow folding and aggregation sensitive in both prokaryotes and eukaryotes. It has been proposed that Hsp70 and Hsp60 chaperone machinery act sequentially, where the previous acts upstream with nascent polypeptide and the latter functions downstream and assists in folding of those substrates which have failed to reach to the final states by Hsp70 alone[16].

    Eukaryotic Hsp60 represents group I chaperonins which includes GroEL found in bacteria, mitochondria and chloroplast with its seven membered ring structure. GroEL functionally cooperates with GroES (Hsp10 in eukaryotes) which forms a lid on the folding cage and together they represent the most extensively studied protein folding machinery[25]. The encapsulated protein folds at the expense of ATP and the folded product is released from the cage again by ATP dependent dissociation of GroES[26]. Another group of eukaryotic chaperonins known as TRiC/CCT, also exhibit an eight membered ring and function independent of the Hsp10 factor[27]. Interistingly, apical domain protrusion of TRiC replaces the role of lid during cage formation[27]. TRiC, with a longer folding time as compared to GroEL folds approximately 10% of the total cytosolic proteins including large multi-domain actin and tubulin proteins[28]. Interestingly, TRiC has also been found to prevent protein aggregation in some protein folding disease models[28]. One of the primary difference between GroEL and TRiC is that the previous acts strictly post-translationally while the later functions co-translationally to fold large proteins of 30 to120 kDa size.

    Role of sHsps and Hsp100 is also crucial in maintaining protein quality and cellular proteome homeostasis. sHsps similar to Hsp40 function independently during ATP reaction cycle[29]. sHsps bind to misfolded proteins and remain bound until they are released to the Hsp70/Hsp40 system, and consequently, prevent the unfolded proteins from aggregate formation[30]. Hsp100 family includes chaperones such as bacterial ClpB, yeast Hsp104 etc. which form another class of ATP driven folding system[31]. In co-operation with Hsp70/Hsp40, the hexametric ring like assemblies of these chaperones perform unfolding reaction followed by refolding of the substrate to attain native conformation[32]. Similar function is performed by Hsp110 in higher eukaryotes which refold and disaggregate the protein aggregates[32].


Molecular chaperones and neurodegenerative disorders

Neurodegenerative disorders are a class of late-onset progressive disorders characterized by presence of misfolded protein aggregates in affected neurons and selective degeneration of the brain. Alzheimer’s disease (AD), Parkinson’s disease (PD) and polyglutamine (polyQ) disorders such as several Spinocerebellar ataxias, Huntington’s disease (HD) etc. represent this category of neurodegenerative disorders. The protein aggregates in each case are formed as a result of protein misfolding which might occur due to genetic or environmental stresses. Most often the disease causing protein undergoes enrichment of the β sheet conformation during misfolding. Interestingly, none of these proteins exhibit β sheet conformation in their wild type state. For instance, Huntingtin (Htt) protein which is responsible for causing HD is a 3140 amino acid protein with a molecular mass of 349 kDa and has been reported to acquire an α-helical/random coil conformation[33]. Similarly, α-synuclein, the major component of Lewy bodies in PD is a 14 kDa protein which although has a low content of ordered structure but adopts a N-terminal α-helical pattern otherwise[34]. In addition, Aβ peptide which is involved in pathogenesis of AD is derived from the proteolytic cleavage of the β-amyloid precursor protein (βAPP) and generally exists as a mixture of β sheet and random coil instead of a full-length β sheet conformer[35].


Formation of protein aggregates -a common link between various neurodegenerative disorders

Conformational changes and protein misfolding result in amyloid-like aggregate formation which is a hallmark of most neurodegenerative diseases. For instance, HD is a dominantly inherited neurodegenerative disorder caused by expansion of CAG trinucleotide repeat in the coding region of the huntingtin (htt) gene[36]. The exact cellular function of Htt is still debatable, however, it has been proposed to participate in vesicular transport and cell signaling[37]. Mutant Htt with expanded poly(Q) repeats tends to misfold and aggregates in the form of inclusion bodies in the cells[38]. Inclusion body formation results in pathological changes in the basal ganglia and cortical neurons of the brain[38]. PD on the other hand is a disorder of the central nervous system caused by mutations in the α-synuclein gene. Types of mutations in cases of PD may range from missense mutations to gene duplication or triplication. These alterations lead to the formation of mutant α-synuclein-containing aggregates known as Lewy bodies, the main pathological feature of PD[39]. Although the precise physiological function of α-synuclein is undetermined, it has been found to be ubiquitously expressed in the entire central nervous system. Subsequently, Alzheimer’s disease (AD) could be characterized as a typical protein misfolding disorder that leads to loss of neurons and synapses in the cerebral cortex and subcortical regions of the brain. AD pathogenesis is resulted by accumulation of misfolded Aβ peptides and the tau protein[40]. While βAPP, the precursor for Aβ, is a transmembrane protein, tau is a microtubule-associated protein. Both undergo abnormal post-translational modifications to give rise to Aβ and hyperphosphorylated tau and form major constituents of disease causing senile plaques and neurofibrillary tangles respectively[41]. Therefore, in view of the fact that protein misfolding serves as the root cause in most of neurodegenerative disorders, next section of the article discusses about major events which lead to disease pathogenesis and also provides a brief overview of the role of chaperones in alleviating aggregate-mediated cytotoxicity.

    The presence of fibrillar protein aggregates marks the signature feature shared by most of the neurodegenerative disorders. Such aggregates were reported for the first time about a century ago by Alios Alzheimer in brain parenchymal tissues of mentally retarded patients[42]. Proteinaceous deposits or aggregates are considered to be the end products of “specific” interactions among partially folded but unstructured protein intermediates[43]. The process of polymerization involves explicit interactions between already deposited initial aggregates, the “seeds” and the newly emerged unfolded monomers[44]. In view of above, it has been proposed that misfolded protein monomers trigger the process of aggregate formation and disease pathogenesis[44]. Several studies suggest that undesirable conformational changes of corresponding proteins underlie the cause of disease pathogenicity[34]. One of the following reasons may result in transformation of a natively folded or even nascent polypeptide chain into a pathogenic misfolded conformation: (a) impairment of chaperone based protein folding machinery due to aging or environmental stresses (eg. wild type α-synuclein in sporadic cases of PD) (b) genetic mutations in the protein coding region of the corresponding gene (eg. CAG expansion in exon 1 of htt) (c) stress mediated atypical post-translational modifications of the target protein (eg. hyperphosphorylation of the tau protein in AD) (d) precursor protein cleavage by proteolytic enzymes (eg. fragmentation of β-amyloid precursor protein in AD) (e) structural modifications driven by environmental changes such as oxidative stress, and (f) induced protein misfolding due to aggregation seeding, cross-seeding mechanisms[45]. The listed events, except for the occurrence of CAG expansion, entail changes in the secondary and/or tertiary structure of the target protein without any variation in the primary structure. This shows that the information needed for protein misfolding (except CAG expansion) is not encoded by the genome in sporadic cases of neurodegenerative disorders. Therefore, the protein aggregates found in neurodegenerative disorders share common structural and biochemical features as per the altered confirmation of the constituent proteins.


Shared mechanism of protein aggregate formation in neurodegenerative disorders

As a nascent polypeptide chain emerges out of the translating ribosome, numerous hydrophobic amino acid stretches get exposed to the cellular milieu, which must be stabilized to ensure non-aggregated states of the protein. At this point, the polypeptide chain can theoretically adopt countless number of conformations out of which only one is sufficiently stable under physiological conditions and could take up the biologically active state. In the case of large and multidomain proteins, partially folded intermediates are produced during the folding process which often causes the “wrong” domains to interact with each other leading to the production of kinetically stable non-native species[43]. These species expose hydrophobic segments to the solvent, an event that sparks off the aggregation process[35]. The equilibrium between the native and non-native species shifts towards the non-native flank when the protein harbors mutations (like CAG repeats) or under conditions of cellular stress or aging.

    As discussed earlier, the process of aggregate formation follows a “seeding nucleation” model consisting of two distinct phases: the slow progressing lag phase and the fast moving log phase[46,47]. The lag phase begins with the misfolded protein taking up an unusual β sheet conformation which initiates filament formation by cooperative aggregation of similar misfolded proteins. Such initial oligomeric assembly serves as a template or “seed” for the elongation process which is said to constitute the log phase of the aggregation process[46,47]. In the log phase, other misfolded protein molecules or even pre-formed seeds are recruited to the initial nuclei leading to rapid polymerisation of the filament and consequent formation of mature fibrillar structures[46,47]. These fibrillar deposits may then be further organized into larger aggregates or amyloid plaques. While aggregates are mostly sequestered and deposited intracellularly in the form of inclusion bodies, amyloid plaques are generally found outside the cell[47]. The intracellular inclusion bodies can be localized both in the cytoplasm as well as in the nucleus. Cytoplasmic inclusion bodies are most frequently deposited at the Microtubular Organisation Centre (MTOC or centrosome)[48]. The inclusion bodies are dense enough to sediment upon low speed centrifugation and could also be observed by light or electron microscopy[49]. Sometimes, the size of the inclusion bodies expands large enough to occupy approximately 30% of the cytosolic area. However, intra-nuclear protein inclusions are key features of most inherited neurodegenerative disorders and have been found to be more toxic than their cytoplasmic counterparts[49]. It has been proposed that neuronal inclusions sequester several key transcription factors through hydrophobic interactions and thus deplete the level of cellular transcriptional machinery[12]. Subsequently, a progressive increase in cellular toxicity may lead to activation of cell death pathways.


Molecular chaperones – handy tools to make or break cytotoxic aggregates

Compromised protein folding apparatus serves as one of the major cause for development of neurodegenerative disorders. Several reports have indicated an early impairment of stress response in most of these disorders[50]. For instance, brain samples of sporadic AD and PD patients have been found to harbour an abnormally S-nitrosylated form of the endoplasmic reticulum (ER) chaperone protein disulphide isomerase (PDI)[51]. As a consequence, the anomalous chaperone is incapable of mounting an efficient ER stress response which is a basic necessity in all protein misfolding disorders. Similarly, a mutation in the gene encoding the co-chaperone for Grp78 (a crucial ER chaperone) has been shown to result in protein accumulation and neurodegeneration[52]. Moreover, mutations in genes encoding members of the Hsp family of chaperones that produce a dysfunctional protein have been found to be associated with several brain related disorders such as Hsp60-linked hereditary spastic paraplegia, Hsp27-linked distal hereditary motor neuropathy, Hsp22-linked distal motor neuropathy, αB-crystallin-linked desmin-related myopathy, etc.[53].

    As discussed earlier, molecular chaperones represent key players of the protein quality control machinery and in this capacity they play essential role in eliminating toxic proteins by inhibiting or promoting the process of aggregate formation. Interestingly, molecular chaperones have been shown to be associated with Htt aggregates as well as with Lewy bodies in brain tissues of affected individuals[54,55]. Moreover, transgenic mouse models of SCA1, 3 and 7 have also been reported to exhibit such association[56]. It has been suggested that chaperones may either block the initial oligomerization of the misfolded proteins by preventing fibril formation or they may promote amyloid formation in an attempt to constrain the toxic species into benign aggregates[57,58].

    As discussed above, parts of the nascent polypeptides emerge out of the ribosome and associate themselves with Hsp70 chaperone to achieve favorable folding and to prevent undesirable interactions. Despite the available safeguards, if protein misfolding occurs due to one of the reasons discussed above, induction of additional Hsps takes place. For example, HeLa cells expressing ataxin-1 or ataxin-3 with expanded polyglutamine repeats exhibit induction of Hsp70[59,60]. Similarly, transgenic mouse models of HD also demonstrated upregulated Hsp levels[61]. In this context it is interesting to note that modulation of various Hsps has been found to function as excellent modifiers of protein misfolding neurodegenerative disorders. For example, overexpression of yeast Hsp70 homolog Ssa1 or Hsp40 homolog Ydj1 suppresses mutant Htt aggregate formation[11]. Similarly, Hsp70 and Hsp40 have been shown to reduce protein aggregation and alleviate neurotoxicity in animal and cell culture models of poly(Q) diseases[60,61]. Independent studies carried out on SCA3 Drosophila model also demonstrated inhibition of neurodegeneration upon targeted overexpression of Hsp70 and Hsp40[62]. Moreover, α-synuclein-induced neuronal loss in a PD model of Drosophila is prevented by the expression of Hsp70[63]. Similarly, Hsp70 and Hsp40-mediated rescue of neurodegenerative phenotype has also been established in cases of familial amyotrophic lateral sclerosis (ALS)[64].

    In addition to Hsp70, other molecular chaperones have also been identified as modulators of neurodegenerative diseases. Hsp104, for instance, has been demonstrated to assist in solubilizing small amyloid-like aggregates in a yeast model of HD[65]. Furthermore, exogenous expression of Hsp104 in C. elegans and rats could also reduce aggregates and mitigates poly(Q) toxicity[66,67]. In addition to its own effect, small Hsps like Hsp26 in yeast and Hsp27 in rats have been shown to potentiate Hsp104-mediated suppression[65,67]. Hsp104 has also proved to be useful in PD rat model where it could exert its modifier effect by antagonizing α-synuclein containing oligomer formation leading to reduced dopaminergic degeneration[68]. Another co-chaperone to Hsp70 - CHIP (carboxy-terminus of Hsp70-interacting protein) is thought to act as an E3 ligase and target misfolded proteins for proteasomal degradation[57]. Over-expression of CHIP in HD and SCA3 cell lines exhibited increased ubiquitination and degradation of Htt and ataxin-3 respectively, which subsequently led to reduced poly(Q) aggregation and also averted cell death[69]. Similar kind of suppression was obtained in studies on primary neurons as well as with zebrafish models[70]. However, in spite of being marked for degradation, some mutant proteins often escape proteolysis and trap 19S subunit of the proteasome into the growing aggregates. This leads to inhibition of the ubiquitin-proteasome system and the eventual cellular dysfunction[71,72]. The cellular proteasomal machinery continues with its efforts to degrade the misfoled protein associated with it and as a result it may release more poly(Q)-containing fragments into the cytosol which in turn enrich the cellular pool of potentially more toxic oligomeric species.

    Interestingly, several studies have reported that molecular chaperones could also promote protein aggregation in an attempt to minimize the presence of soluble oligomers in the cell. For example, HDJ2 (a human Hsp40 homologue), caused enhanced aggregation of mutant Htt in Cos-7 cells[73]. Likewise, chaperones belonging to the proteasomal machinery like Rpt4 and Rpt6 have also been shown to facilitate the process of aggregation for expanded-poly(Q) Htt as well as ataxin-3 proteins[74]. Similarly, TRiC (TCP-1 ring complex) chaperonin has been demonstrated to increase amyloid aggregation and suppress poly(Q) mediated toxicity in C. elegans, yeast and cell culture[75-77]. It has been demonstrated in yeast poly(Q) model that TRiC in conjunction with Ssa1 and Ydj1 could boost the conversion of low molecular weight soluble oligomers into high molecular weight aggregates which coincided with suppression of poly(Q) induced toxicity[76].

    Chaperones could also eliminate misfolded proteins by a unique type of autophagic mechanism known as Chaperone-mediated autophagy (CMA). CMA entails the use of a membrane translocation complex for delivery of the target proteins to the lysosomal lumen rather than canonical vesicles[78]. A recent study has found Hsp70 as an important player of this process[79]. Hsp70 may operate with other co-chaperones like Hsp40, Hsp90, hip, hop, and bag1 to facilitate aggregate clearance via CMA[79,80]. Among the proteins involved in neurodegenerative disorders, α-synuclein was the first to be identified as a substrate for CMA[81]. These findings were later confirmed by studies on neuronal cell cultures as well as on model systems. Similarly, Htt cleavage products as well as mutant form of Htt were found to be the targets of CMA[82]. Intriguingly, CMA dysfunction has been shown to be associated with several neurodegenerative disorders[83]. In concordance with this observation, genetic upregulation of CMA proved to be protective against neurotoxicity[84,85].


Concluding remarks

In brief, molecular chaperones not only assist in accurate folding of nascent polypeptide chains and denatured proteins but also participate in damage control in many neurodegenerative diseases. Several studies on model organisms including Drosophila, C. elegans and mice have shown that induction of chaperones can ameliorate disease pathogenicity either by preventing protein misfolding and aggregation or by promoting aggregate formation so that the abnormal proteins could be isolated in inclusions. In doing so, they may perform refolding events or direct members of the proteasome machinery to the site of damage. Therefore, molecular chaperones occupy an important position in the list of probable genetic modifiers for neurodegenerative diseases, and therefore, are being considered as a promising choice for development of novel therapeutic strategies against neurodegenerative disorders. In fact, several studies have reported beneficial effects on disease symptoms upon administration of chaperone-inducible drugs. However, mechanistic details of chaperone action remain elusive. Further studies are needed to be carried out in the above area. Attempts should also be made to decipher the role of molecular chaperones as well as ubiquitin-proteasome system with respect to age-dependent progression of neurodegenerative phenotypes. Such a collective approach may help design effective treatment strategies against these devastating human disorders.



Research programs in laboratory are supported by grants from the Department of Biotechnology (DBT), Government of India, New Delhi; Department of Science and Technology (DST), Government of India, New Delhi, and Delhi University R & D fund to SS. KR and SIC are supported by Junior Research Fellowship (JRF) and Senior Research Fellowship (SRF) respectively from the University Grant Commission (UGC), New Delhi.



The Authors have no conflicts of interest to declare.



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Peer reviewer: Mansoureh Hashemi, Neuroscience Department, School of advanced Technologies in Medicine, Tehran University of Medical Sciences, Keshavarz Boulevard, qods Street, Italia Street, Tehran, Iran



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