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
Email: sarkar@south.du.ac.in
Telephone: +91-11-24112761
Received: December 22,
2014
Revised: March 3, 2015
Accepted: March 9, 2015
Published online: May 13, 2015
ABSTRACT
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:
http://www.ghrnet.org/index.php/ijnr/article/view/1065
INTRODUCTION
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.
Acknowledgements
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.
CONFLICT OF INTERESTS
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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