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Chaperone-dependent Neurodegeneration: A Molecular Perspective on Therapeutic Intervention

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Maintenance of cellular homeostasis is regulated by the molecular chaperones. Under pathogenic conditions, aberrant proteins are triaged by the chaperone network. These aberrant proteins, known as "clients," have major roles in the pathogenesis of numerous neurological disorders, including tau in Alzheimer's disease, α-synuclein and LRRK2 in Parkinson's disease, SOD-1, TDP-43 and FUS in amyotrophic lateral sclerosis, and polyQ-expanded proteins such as huntingtin in Huntington's disease. Recent work has demonstrated that the use of chemical compounds which inhibit the activity of molecular chaperones subsequently alter the fate of aberrant clients. Inhibition of Hsp90 and Hsc70, two major molecular chaperones, has led to a greater understanding of how chaperone triage decisions are made and how perturbing the chaperone system can promote clearance of these pathogenic clients. Described here are major pathways and components of several prominent neurological disorders. Also discussed is how treatment with chaperone inhibitors, predominately Hsp90 inhibitors which are selective for a diseased state, can relieve the burden of aberrant client signaling in these neurological disorders.
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Chaperone-dependent Neurodegeneration: A Molecular
Perspective on Therapeutic Intervention
Aaron Carman1, Sarah Kishinevsky1, John Koren III1, Wenjie Lou2, and Gabriela Chiosis1,*
1Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer
Centre, New York, NY, USA
2Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY, USA
Abstract
Maintenance of cellular homeostasis is regulated by the molecular chaperones. Under pathogenic
conditions, aberrant proteins are triaged by the chaperone network. These aberrant proteins,
known as “clients,” have major roles in the pathogenesis of numerous neurological disorders,
including tau in Alzheimer’s disease, α-synuclein and LRRK2 in Parkinson’s disease, SOD-1,
TDP-43 and FUS in amyotrophic lateral sclerosis, and polyQ-expanded proteins such as
huntingtin in Huntington’s disease. Recent work has demonstrated that the use of chemical
compounds which inhibit the activity of molecular chaperones subsequently alter the fate of
aberrant clients. Inhibition of Hsp90 and Hsc70, two major molecular chaperones, has led to a
greater understanding of how chaperone triage decisions are made and how perturbing the
chaperone system can promote clearance of these pathogenic clients. Described here are major
pathways and components of several prominent neurological disorders. Also discussed is how
treatment with chaperone inhibitors, predominately Hsp90 inhibitors which are selective for a
diseased state, can relieve the burden of aberrant client signaling in these neurological disorders.
Keywords
Neurodegeneration; Molecular chaperones; Aberrant neurological proteins; Chaperone inhibitors
Introduction
Chaperones in disease
Eukaryotes have evolved elaborate systems of chaperone proteins to cope with cellular
stress. Under normal cellular conditions, chaperones regulate nascent protein folding.
Cellular stressors, such as a thermal stress, can cause proteins to become unfolded, non-
Copyright: © 2013 Carman A, et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
*Corresponding author: Gabriela Chiosis, Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer
Centre, New York, NY, USA, chiosisg@MSKCC.ORG.
Competing Interests Statement
MSKCC holds the intellectual rights to the method of use of purine-scaffold Hsp90 inhibitors in the treatment of neurodegenerative
diseases.
NIH Public Access
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Published in final edited form as:
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functional, or even structurally damaged. To maintain cellular homeostasis, the chaperone
network will interact with these damaged “client” proteins and attempt to fold the protein
back into a functional state or target the client for degradation. However, certain mutated or
abnormally-modified disease-causing proteins are stabilized and maintained by the
multitasking heat-shock protein 90 (Hsp90) and its co-chaperone network [1-3]. Such is the
case in certain cancers, where the Hsp90 chaperone network facilitates disease by stabilizing
oncogenic client proteins. It is now becoming clear that Hsp90 and its co-chaperones also
regulate a majority of neurodegenerative proteinopathy (Figure 1 and Table 1).
A role for Hsp90 in the maintenance of neurodegenerative diseases is thought to be similar
to its proposed role in cancer: mis-folding or stabilization of aberrant (neurotoxic) client-
proteins. Because Hsp90 client-protein folding (and stabilization) is ATP-dependent, Hsp90
activity can be manipulated by ATP competitive small molecules. Indeed, the first known
Hsp90 inhibitor, the antibiotic geldanamycin (GA), was discovered to compete with ATP for
binding which stops the protein folding cycle and prevents client stabilization [4-7].
While these important biological roles propose a role for Hsp90 inhibitors in the treatment
of neurodegenerative disease, it is also true that Hsp90 is one of the most abundantly
(~1-3% of total cellular protein) and ubiquitously expressed proteins. Such finding matches
poorly with the belief that a good therapeutic target has to be of low expression in vital
organs and tissues. Using the GA derivative 17-allylaminogeldanamycin (17-AAG), Kamal
et al. provided the rationale for a therapeutic index for the use of Hsp90 inhibitors in disease.
Specifically, they demonstrated the presence of high-ATP-affinity Hsp90 complexes
seemingly exclusive to diseased cells. High-affinity species bound to these small-molecule
ATPase inhibitors with nearly 100-fold higher affinity than Hsp90 from non-cancer cells [8].
This finding made GA, and similar inhibitors, both potently selective and therapeutically
attractive.
Further work by Moulick et al. demonstrated that only a small percentage of the total
cellular Hsp90 population exists in this high-affinity state [9]. It is thought that as the levels
of intracellular aberrant proteins rise, so does the need for Hsp90; the cell’s attempt to deal
with accumulating proteins depends on greater Hsp90 activity. While the complete nature
and composition of this high-affinity Hsp90 complex remain unclear, post-translational
modifications [10] and binding of co-chaperones [9] to Hsp90 are likely involved. The shift
to greater ATP- affinity and increased activity promotes the stabilization of pools of aberrant
protein clients, possibly by passing them through folding cycles that are ultimately
unproductive, stabilizing species whose fate should be degradation. This process facilitates
and maintains many cancers and, as we show further here, many neurodegenerative diseases
as well.
Aberrant proteins become clients of Hsp90 or are regulated by the Hsp90 chaperone network
[9]. As mutant proteins continue to be experimentally recapitulated in cellular and animal
models, much has been learned about the pivotal role of Hsp90 and its extensive co-
chaperone network in the stabilization of aberrant client proteins. We will begin this review
by examining tau as a model Hsp90 client, including the crucial role of Hsp70 in tau
pathology.
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These ideas will serve as a framework for subsequent discussion of aberrant proteins in
other neurodegenerative diseases. We will evaluate experimental results from various
cellular and animal disease models and discuss the therapeutic potential of pharmacologic
intervention at the chaperone level. Lastly, we will propose a general model of chaperone
dependency that links much seemingly-disparate neurodegenerative pathologies (Figure 2).
Hsp90/Chaperone-dependent Tauopathies
Tau in neurodegeneration
The microtubule associated protein tau (MAPT) is a focal point of cellular regulation that
integrates and responds to input from converging signaling cascades to regulate microtubule
dynamics. Loss of microtubule function is detrimental to multiple neuronal systems
including axonal transport, mitochondrial function, and autophagy [11-13]. In disorders
featuring aberrant tau, a group collectively known as tauopathies, microtubule dysfunction is
a common feature and this dysfunction has been suggested to be an initiating factor for the
accumulation of tau. Tau affinity for microtubules is largely regulated by site-specific
phosphorylation. The N-terminal acidic domain and C-terminal microtubule binding domain
of tau flank a proline-rich middle region that is a target for pathogenic hyperphosphorylation
by many proline-directed tau kinases. Tau exists as six isoforms each of which has a
different affinity for microtubules [14,15]. Two predominant groups are comprised of tau
isoforms containing 3 or 4 microtubule-binding domain repeats in the C-terminus (3R or
4R). Tau mutations altering the 3R/4R tau ratio, normally about 1:1 [16], perturb tau
proteostasis and can lead to microtubule destabilization and disease [17].
The phosphorylation and isoform specifics of tau are not the only factors that may drive tau
pathogenicity. Tau mutations are responsible for a diverse group of neurodegenerative
dementias that include Pick’s disease, progressive supranuclear palsy (PSP) [18,19],
corticobasal degeneration (CBD) [20-22], and fronto-temporal dementia with parkinsonism
linked to chromosome-17 (FTDP-17), a rare but devastating disease [23]. These disease-
linked tau mutations affect tau phosphorylation and dephosphorylation [24,25], which then
alter tau affinity for microtubules [26-32]. These mutations also change the predilection of
tau to aggregate into paired-helical filaments (PHF) and neurofibrillary tangles (NFT)
[33-35]. For example tauP301L and tauP301S, two commonly-studied mutations, have each
been linked to FTDP-17 [23,36,37]. Transgenic mice expressing human tau with these
mutations accumulate hyperphosphorylated, insoluble tau and undergo cognitive and motor
decline [38-44]. To date, more than 37 tau mutations have been associated with FTDP-17
[45]. Although NFTs comprised of insoluble tau are a hallmark of Alzheimer’s disease, no
tau mutations have yet been associated with AD. Finally, accumulation of tau and other
neuronal disease-related proteins is thought to be exacerbated by age-dependent decline in
protein degradation, as deficits in proteasomal processing and autophagy are observed in
aging brains [46].
Perhaps the most remarkable aspect to tau pathogenesis is the fact that mutant tau fibrils can
spread from cell to cell and confer a pathogenic conformation to normal tau, a process
similar to intercellular prion seeding [47,48]. Upon selective expression of tauP301L in the
entorhinal cortex of mice, the origin of tau pathology in AD [49], pathogenic tau spread
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trans- synaptically through neuronal circuits in a temporal and spatial progression that
mimics human disease [50]. These findings support the importance of developing reliable
early diagnostic techniques for tau and also point to multiple steps of potential therapeutic
intervention. As we shall see, they also raise questions about which steps are facilitated by
chaperones.
In neurons, the breadth of tau function underlies the impact of its loss, or the loss of its
normal functions. Once thought to be without phenotype because of redundancy found in
related microtubule-binding proteins, tau knockout mice were recently shown to develop
age- dependent brain atrophy and “parkinsonism-like” symptoms [51]. Interestingly, this
degeneration was associated with a diminished neuronal iron transport mediated by amyloid
precursor protein (APP), the protein processed into the aggregation-prone β-amyloid (Aβ) in
Alzheimer’s disease. Although neither APP nor Aβ has been confirmed as a bone fide
Hsp90 client, in vitro studies suggest Aβ peptide aggregation can be influenced by Hsp90
and its co-chaperone Hsp70 [52,53]. Additionally, studies in HEK cells suggest CHIP,
Hsp70 and Hsp90 all participate in APP metabolism [54]. The Hsp90 chaperone network
might also regulate drivers of Aβ production or aggregation [54,55]. Importantly, most
current models of AD pathology support a role for Aβ as a driver of tau pathology [56,57]
and a role for tau as the primary mediator of accumulating Aβ toxicity [58-60]. While the
exact role of Hsp90 in Aβ pathology in AD remains unclear, Hsp90 and its co-chaperones
play critical roles in facilitating tau pathology.
Hsp70/90 regulation of Tau proteostasis
The first clues to Hsp70 and Hsp90 involvement in tau/microtubule regulation came in 2003
with the demonstration that higher levels of Hsp70 and Hsp90 correlated with lower levels
of insoluble tau and increased tau-microtubule association [61]. In 2007, “high-ATP-
affinity” Hsp90 complexes were discovered in the temporal cortex (an affected area) but not
in the cerebellum (an unaffected area) of post-mortem brains from AD patients [62].
Before tau encounters Hsp90, though, it is bound by either Hsc70 or Hsp70, which control
tau access to the proteasomal degradation machinery, the “triage decision”. Following
microtubule destabilization, tau first binds to the constitutively-expressed co-chaperone
heat-shock cognate protein-70, Hsc70 [63]. Once this complex has formed, the aberrant
client protein faces one of two fates: either folding or degradation. The client could be
presented to Hsp90 through the scaffolding co-chaperone HOP (Hsp70/Hsp90 organizing
protein) for attempted folding. Hsp90 interaction with either Hsc70 or Hsp70 may play
opposing roles in facilitating accumulation of problem clients like tau: Hsc70 binding
appears to stabilize tau and shelter it from degradation [63]. Also, the multi-functional
modulator Bcl2-associated athanogene-1 (BAG-1) associates with the tau-Hsc70 complex
and actually prevents proteasomal degradation of tau, a situation reversed by Hsp70
induction [64]. Hsp70-bound tau can be ubiquitinated by the E3-ubiquitin ligase CHIP
(Hsc70-interacting protein) and targeted for proteasomal degradation [62,65-68]. These
finding suggest Hsp70 binding may favour tau degradation, whereas Hsc70 binding favours
folding. Hsp70 and Hsc70 have been shown to have these opposing effects on other client
proteins, as well [69]. These ideas are consistent with findings that Hsp70 differentially
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regulates tau isoforms and may function primarily in regulating dysfunctional tau isoforms
[70].
Elegant biochemical studies by Kundrat and Regan demonstrate that CHIP binding to the
Hsp70-client complex excludes HOP-Hsp90 binding [68]. Their in situ and in vitro analyses
indicate that inhibition of Hsp90 causes client proteins to be degraded due to the expansion
of the degradation pathway. Low cellular levels of Hsp70 and CHIP may control the basal
levels of “house-keeping” turnover and degradation of tau, a pathway that is better accessed
by tau when more Hsp70 is available to present tau to CHIP.
The potential for tau pathogenesis is also regulated by phosphorylation. This phospho-
regulation of tau runs directly through the Hsp90 chaperone network. By chaperoning client
kinases like glycogen synthase kinase (GSK3β), p35/CDK5 and microtubule affinity
regulating kinase-2 (MARK2), three established tau kinases, the Hsp90 network controls the
flow of signaling input to tau [53,71-73]. Hsp90 co-chaperones like the immunophilin
FKBP51/2 regulate tau folding and mediate kinase access to tau [74,75], while another
Hsp90 co- chaperone, protein phosphatase 5 (PP5), is a major tau phosphatase [73]. Thus
Hsp90 acts as a nucleus for the complex regulatory machine that controls much of tau
biology.
Chaperone Inhibition in Alzheimer’s Disease and Tauopathy
Inhibition of Hsp90
The most promising Hsp90 inhibitors target the N-terminal ATPase domain [76-79]. Many
novel and synthetic Hsp90 inhibitors are already in clinical trials, but at this point they are
being tested primarily in cancer [80-82]. Research in the last decade revealed the therapeutic
potential of Hsp90 inhibition in proteinopathic neurodegeneration [83,84]. In early 2007,
two studies demonstrated that Hsp90 inhibition decreases levels of hyperphosphorylated
and/or mutated tau in cells and transgenic mice. Using the inhibitor EC102, Dickey et al.
demonstrated selective degradation of hyperphosphorylated tau in both cells over-expressing
tauP301L and in the human tau (hTau) mouse model [62,85], which expresses all 6 human
isoforms of tau and develops NFT and “Alzheimer-like” pathology [86]. Additionally,
Hsp90 inhibition with EC102 selectively decreased tau phosphorylated at Ser/Thr sites
thought to be controlled by the proline-directed kinases, likely GSK-3β and Cdk5
[62,85,87,88]. Both kinases are known to participate in pathogenic tau phosphorylation
while Akt, working with CHIP, also regulates tau degradation [89].
Also in early 2007, Luo et al. demonstrated that 17-AAG and the brain-permeable synthetic
purine scaffold Hsp90 inhibitor, PU-DZ8, decreased levels of phosphorylated tau [90].
Importantly, not only does Hsp90 inhibition decrease levels of tau specifically
phosphorylated on Ser202, a pathogenically-important site known to be phosphorylated by
Cdk5, but also levels of the Cdk5-activator protein p35, which is itself a client of the Hsp90
chaperone network. Interestingly, while treatment of tauP301L mice with PU-DZ8 resulted
in decreased soluble and insoluble tau, including mutant tau, treatment of hTau mice
decreased Ser202-phosphorylated tau without affecting levels of endogenous tau [90].
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As discussed, inhibition of Hsp90 in a system flooded with mis-folded client proteins has
multiple beneficial effects. First, Hsp90 inhibition eliminates the folding pathway as an
option for aberrant tau increasing the probability that tau will be ubiquitinated by CHIP and
degraded. Second, Hsp90 inhibition initiates the HSF1-dependent heat-shock response and
subsequent induction of Hsp70 and small heat-shock-protein (sHSP) [91]. Induction of
Hsp70, normally expressed at very low levels, may increase tau degradation by out-
competing Hsc70 for tau binding, thus giving aberrant tau a better chance at being
ubiquitinated by CHIP, an E3 ubiquitin ligase (Figure 1). Small HSP induction, particularly
that of Hsp27, can also benefit neurons plagued with aberrant tau as recent work
demonstrated that, when functional, Hsp27 was able to reduce tau burden in a transgenic-tau
mouse model [92]. Hsp27 has also been shown to have neuroprotective effects against other
drivers of AD pathology [93]. And third, many kinases that regulate tau are also clients of
Hsp90. Indeed, it was recently shown that Hsp90 inhibition particularly impacts kinase
stability [94]. Hsp90’s role as a signaling node, connecting many regulatory pathways and
regulating disease-specific processes, adds to its potential as a therapeutic target for
inhibition in tau-based neurodegeneration: not only can the hyperphosphorylated tau be
reduced but the kinases contributing to its persistent hyperphosphorylation can also be
down-regulated. Thus, Hsp90 inhibition potential has greater efficacy than therapeutics that
target single players in the processing pathways of these pathogenic proteins. When
considered with decreased proteasome function or defective autophagy, as is suspected to
occur in AD and many other neurodegenerative conditions [95-98], Hsp90 inhibition could
reduce the tau burden from an overburdened and dysregulated regulatory system. As will be
discussed later, similar regulatory systems may control the fates of other neurodegenerative
proteins.
While these studies demonstrate the molecular effects of Hsp90 inhibition on tau
degradation, validation of this therapeutic approach awaits the results of experiments
designed to test these inhibitor’s abilities to prevent and/or improve cognitive and
behavioural deficits associated with tauopathies. Exactly how tau reduction will impact
these functions is still unclear. Much will depend on the timing and duration of therapeutic
intervention and how much neuronal damage has already occurred. These studies also
highlight the critical role of Hsp90 in facilitating neurodegenerative phenotypes and they
demonstrate how Hsp90 inhibition affects select client proteins through multiple pathways.
Therapeutic modulation of Hsp70 in AD
Controlling the expression and activity of Hsp70 shows some promise in vitro and in cell
models of tau-based neurodegeneration. Work from Dickey’s group has identified both
activators and inhibitors of Hsp70 activity [65,69,99-101]. Activation of Hsp70 increased
tau stability, possibly by passing tau through an unproductive folding cycle. Conversely,
Hsp70 inhibition reduced tau levels in cell-based models, perhaps by locking client tau and
Hsp70 together, resulting in their ubiquitination and degradation [99]. They hypothesized
that Hsp90 inhibition and the subsequent induction of Hsp70, followed by Hsp70 inhibition
might be a potent strategy at reducing aberrant tau levels [65,99].
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It is important to note, however, that Hsp70 proteins are well-characterized protectors
against stress-induced apoptosis [102-104]. Hsp70 and Hsc70 silencing seems to sensitize
cancer cells to Hsp90 inhibition by reducing pro-apoptotic signaling [105]. While apoptotic
outcomes are desirable in cancer, it seems unlikely that widespread neural apoptosis would
benefit neurodegenerative diseases like AD. Indeed, Hsp70 limits apoptosis in neurons
expressing mutant androgen receptor, the protein responsible for SBMA [106]. Thus
strategies that inhibit Hsp70, especially after Hsp90 inhibition, may increase the risk of
neural apoptosis. It will be important for future studies to determine the possible therapeutic
risks and benefits of Hsp70 inhibition in patients with tauopathy.
Chaperones in Parkinson’s Disease
Alpha-synuclein, LRRK2 and the chaperone network
Alpha-synuclein is highly abundant in the pre-synaptic terminals of brain tissue [107]. It
comprises the primary fibrillar component of Lewy body inclusions commonly found in
Parkinson’s disease (PD) patient brains [108] and its transgenic overexpression in mice
facilitates neurodegeneration [109-112]. Postmortem analysis revealed that Hsp90, Hsc70
and Hsp40 co-localized with α-synuclein in Lewy bodies of α-synucleinopathy patients
[113] and that CHIP and Hsp70 co-localized with α-synuclein in Lewy bodies of DLB
patients [114]. Like tau, α-synuclein is an intrinsically disordered protein and can form
oligomeric species that differ in size and shape [115] some of which can be toxic [116-118].
Mutations that promote α-synuclein aggregation [119-124] and α-synuclein duplications
cause familial PD [125,126]. Further, Hsp90, Hsp70 and CHIP interact with α-synuclein.
Hsp90 can influence α-synuclein aggregation and vesicle binding; as was demonstrated in in
vitro studies where Hsp90 binding to α-synuclein both abolished the ability of α-synuclein
to bind to small unilamellar vesicles and promoted fibril formation in an ATP-dependent
manner via oligomeric intermediates [127]. Indirect data support the notion that Hsp70
likely binds monomeric forms of soluble α-synuclein: following Hsp70 depletion, α-
synuclein reactions resumed at a rate similar to the initial monomer-containing reactions
[128]. CHIP, by co-immunoprecipitation, was also shown to interact with α-synuclein and
Hsp70 in transfected H4 cells [129]. CHIP overexpression also reduced high molecular
weight α-synuclein oligomers as well as mediated α-synuclein degradation via both
proteasomal and lysosomal pathways in H4 cells [129]. While the field continues to explore
possible mechanisms of α-synuclein-induced toxicity, in vitro studies suggest that Hsp90,
Hsp70 and CHIP likely interact in a dynamic process to regulate α-synuclein fibril assembly
and degradation.
Intraneuronal inclusions found in Parkinson’s patients can also contain leucine-repeat- rich
kinase 2 (LRRK2). The LRRK2G2019S substitution is the most common sporadic and
inherited PD-causing mutation and is associated with dominantly inherited PD [130-133].
Mechanisms similar to, yet distinct from, α-synuclein aggregation may govern the function
and stability of LRRK2 in Parkinson’s disease. As with α-synuclein, Hsp90, Hsp70 and
CHIP also interact with LRRK2. Several LRRK2 proteomic studies have independently
verified that LRRK2 binds to Hsp90 [134-137]. Lichtenberg et al. found that Hsp70
overexpression in COS-7 cells decreased LRRK2 aggregation [138] but did not influence
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levels of soluble LRRK2. LRRK2 expression in Zebrafish embryos increased GFP
ubiquitination. The authors suggested that LRRK2 is more accessible in the presence of
Hsp70 and that certain LRRK2 species, such as LRRK2 mono- or oligomers may mediate
the accumulation of other proteins. CHIP can bind to multiple LRRK2 domains and promote
LRRK2 degradation in HEK293 cells [134]. Further, Hsp90 and CHIP activity levels are
determinants of LRRK2-mediated toxicity [134,139]. CHIP overexpression and increased
LRRK2 degradation rates in HEK293 cells [134] and also reduced LRRK2-mediated
toxicity in SH-SY5Y cells and HeLa cells.
Hsp90 inhibition in parkinson’s disease models
Multiple in vitro studies determined that small molecule Hsp90 inhibitors have the potential
to treat Parkinson’s disease. In human H4 neuroglioma cells, Hsp90 inhibitors reduced α-
synuclein-induced toxicity [140,141]. Hsp90 inhibitors also rescued the axonal growth
retardation caused by LRRK2G2019S in primary mouse cultured cortical neurons [142].
Additionally, Hsp90 inhibition reduced the toxicity mediated by LRRK2G2019S and
LRRK2R1441C in transfected HeLa cells [139].
In vivo studies in PD models have been limited, perhaps largely because researchers are still
in the process of developing and refining effective brain-permeable Hsp90 inhibitors. Hsp90
inhibitors prevented α-synuclein oligomer formation in culture [140] but the in vivo effects
on α-synuclein have not been reported. Hsp90 inhibition rescued α-synuclein induced
toxicity in Drosophila [84]. Further, a MPTP-damage mouse model of PD also revealed
neuroprotective effects of Hsp90 inhibition [143].
While Hsp90 inhibitors have shown great promise for reducing protein levels, it is important
to note that a number of PD-causing mutations are the result of inactive or under-
functioning domains. For example, PTEN-induced kinase 1 (Pink1) PD-causing mutations
likely reduce Pink1 activity [144-146] are linked to familial PD and Pink1 haplo-
insufficiency is linked to idiopathic PD [147-149]. Pink-1 is an Hsp90 client [150,151] and
its function may rely partly on its interaction with Hsp90. Additionally, loss-of-function
mutations in parkin, an E3 ubiquitin ligase similar to CHIP, are causative factors in some
familial PD [152]. If loss-of-function proteins are drivers of α-synucleinopathies like
Parkinson’s disease, the potential in vivo benefits of Hsp90 inhibitors still exist as Hsp90
inhibition drives pro-clearance pathways regardless of client functionality.
In addition to directly modulating Hsp90 clients, Hsp90 inhibitors may exert indirect
protective effects resulting from HSF-1 activation and subsequent Hsp70 induction. In
Drosophila and yeast models of PD, directed expression of Hsp70 or heat shock
(presumably through Hsp70 induction) limited α-synuclein cytotoxicity [84,153]. Hsp70 can
also prevent pre- fibrillar α-synuclein formation [128,154] and reduce LRRK2 aggregation
[138].
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Chaperones and Amyotrophic Lateral Sclerosis ALS
Amyotrophic lateral sclerosis (ALS) is a fatal degenerative disease of upper and lower motor
neurons and the average lifespan for patients with ALS is only 3-5 years after diagnosis.
Currently, over 250 mutations in 11 genes have been linked to a spectrum of familial (fALS)
and sporadic forms of ALS [155,156]. Once thought to be more than 95% sporadic, it has
been argued that many fALS cases are likely misreported as sporadic and should more
properly be referred to as isolated ALS (iALS) [155]. Recent molecular analyses indicate a
majority of familial ALS is caused by mutations in one of three proteins: the Cu/Zn
superoxide dismutase SOD1 or one of two RNA-processing proteins, TAR-DNA-binding
protein-43 (TDP-43) or fused- in-sarcoma (FUS), the last two of which are also linked to
FTLD [157]. As with tauopathies and Parkinson’s disease, evidence supports a chaperone-
mediated hypothesis of disease for much of ALS. Most importantly, therapeutic strategies
that inhibit Hsp90 and increase Hsp70 activity show promise in some cellular and animal
ALS models.
SOD1
Since mutant SOD1 was first associated with insoluble intracellular inclusions from familial
ALS (fALS) patients [158], it is now estimated that 20% of fALS is associated with SOD1
mutations [159]. SOD1 normally protects cells from oxidative damage, dismutating the free
radical superoxide to oxygen and hydrogen peroxide. Disease-related SOD1 mutations are
thought to confer a gain-of-function, as mice expressing dismutase-inactivated SOD1
develop ALS [160]. While many theories have been proposed to explain SOD1-mediated
neurodegeneration, it likely arises from disruption of multiple cellular systems including
metabolic signaling and metal homeostasis [161,162]. Interestingly, the contribution of
aberrant SOD1 to disease depends on the cell type expressing SOD1: neuronal SOD1
influences disease genesis while astrocyte and microglial expression can accelerate disease
progression [163-166].
Similar to aberrant proteins in other neurodegenerative diseases, mutant SOD1 is a client of
the Hsp70/Hsp90 chaperone network [167], and its proteasomal degradation is largely
regulated by the ubiquitin ligase CHIP [167-169]. Ubiquitinated SOD1 is a primary
component in the intraneuronal aggregates in some ALS [158]. Hsc70 is commonly found
associated with these aggregates [170,171]. This might suggest the possibility of a situation
similar to that of tau and Hsc70 [64]: Hsc70 might protect SOD1 from proteasomal
degradation and facilitate its accumulation [64], while Hsp70 binding might favor SOD1
ubiquitination and degradation. In cultured motor neurons expressing mutant SOD1,
increasing levels of Hsp70 decreased aggregation of SOD1 and attenuated toxicity
[172,173]. Raising Hsp70 levels by overexpression [174], increased HSF-1 activity or
Hsp90 inhibition with 17-AAG was cytoprotective and decreased mutant SOD1 levels in
primary motor neuron cultures [175]. Conversely, Liu et al. reported no benefit from over-
expression of Hsp70 in mutant SOD1 mice [176]. Taken together, these results might
suggest that in cellular models of SOD1-based ALS, increasing Hsp70 activity is sufficient
to decrease SOD1 aggregation and limit neurotoxicity. However, in vivo models of ALS
appear to benefit more from the induction of a generalized Hsf1-dependent heat-shock
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response. The compound arimoclomol, a “co-inducer” of the heat- shock response, reduced
aggregated SOD1, delayed disease progression and increased lifespan in mutant SOD1 mice
[177,178]. Recent Phase II and Phase III clinical trials with arimoclomol in SOD1-fALS
patients ended and the results are expected in the near future.
TDP-43 and FUS
A break-through in our understanding of ALS began last decade when insoluble,
ubiquitinated RNA-binding protein TDP-43 was discovered in patients with ALS and FTLD
[179,180]. Soon thereafter, mutated TDP-43 was linked to both fALS and iALS [181-183].
After mutations in a structurally similar RNA-binding protein, FUS, were also linked
causatively to fALS [184,185], RNA processing gained wider attention in neurodegenerative
research. Many recent studies implicate both loss- and gain-of-function toxic effects in
TDP-43/FUS pathogenicity. TDP-43 normally regulates expression and splicing of mRNA
transcripts longer than 1000 kilobases [186], including transcripts for proteins involved in
synaptic function like the N-methyl-D-aspartate (NMDA) receptor and transcripts for
proteins implicated in neurodegeneration like tau, parkin, huntingtin, the ataxin proteins and
FUS [186-188]. TDP-43 and FUS are binding partners that may act in concert to promote
toxicity. ALS-linked TDP-43 mutations increase protein stability and increase its association
with FUS [189]. A complex of the two proteins inhibits cell growth in yeast [190] and
impacts movement and lifespan in Drosophila [191], effects possibly mediated by co-
regulation of histone deacetylase 6 (HDAC6) mRNA [192].
TDP-43 disease pathology appears to be controlled by the Hsp90 chaperone network. In a
Drosophila model of ALS, 17-AAG treatment decreased and redistributed TDP-43 and
decreased levels of its toxic proteolytic product TDP-25 [193]. Indeed, neurotoxicity of the
TDP- 43A315T mutant in Drosophila was mitigated by Hsp70 over-expression [194]. These
results suggest a regulatory role for Hsp70 and Hsp90 in TDP-43 proteostasis and
pathogenicity either directly or indirectly. While much remains to be elucidated about the
nature and regulation of these disease-causing proteins, these studies highlight the
importance of Hsp90 and its extensive co-chaperone machinery in ALS disease processes.
Chaperones and Polyglutamine Diseases
Some of the earliest clues to chaperone involvement in neurodegeneration came when the
Hsp90 co-chaperones Hsp70 and Hsp40 were linked to polyglutamine-expansion (polyQ)
diseases. These neurodegenerative diseases involve cytotoxic accumulation of a mutated
protein that contains expanded tracts of glutamine residues. Increased CAG nucleotide
repeats forming a series of uninterrupted glutamines disrupts native protein structure and
promotes aggregate formation.
Polyglutamine expansion of ataxin proteins causes spinocerebellar ataxia (SCA), a spectrum
of progressive neurodegenerative diseases currently attributed to mutations in over 29 genes
[195]. Much evidence suggests the Hsp90 chaperone network regulates mutant ataxin
biology. Early results from cell models demonstrated Hsp70 and Hsp40 prevented in situ
aggregation of mutant ataxin-1 (SCA1) [196]. Overexpression of Hsp70 was also shown to
provide neuroprotection in two in vivo models of CAG-expansion ataxia [197,198]. The
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proteasomal degradation of both ataxin-1 and ataxin-3 is controlled by CHIP-ubiquitination
[199-202], an interaction mediated under stress conditions by Hsp70 [199]. Samples taken
from patients with spinocerebellar ataxia type-7, another polyQ disease brought on by CAG
repeats, demonstrated decreased expression of two major heat shock proteins, Hsp70 and
Hsp27 [203]. Other groups have also demonstrated that expression of Hsp70 can be
beneficial, or lack-there- of detrimental, in select polyQ ataxin disorders [204,205]. The
observed neuroprotection combined with the genetic suppression suggests that induction of
Hsp70 could be beneficial in cases of polyQ expanded ataxins.
Chaperone modulation also limited aggregation of mutant polyQ androgen receptor in
cellular models of spinal and bulbar muscular atrophy (SBMA) [106,206], a slowly-
progressive X-linked neurodegenerative disease. In 2005, Waza et al. provided the first
evidence of high- ATP-affinity Hsp90 in neurodegenerative disease, when they showed 17-
AAG bound to a complex of Hsp90 and mutant androgen receptor in both cellular and
mouse SBMA models [207]. Additionally, treatment with the orally-bioavailable GA
derivative 17- (dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) limited
cellular damage and improved motor function in SBMA mice [208]. It is important to note
that Hsp90 inhibition caused specific degradation of mutant androgen receptor and did not
affect levels of wild-type receptor. Perhaps not surprisingly, Hsp90 inhibition prevented
aggregation of mutant androgen receptor in a cellular model that lacked Hsf1 and could not
initiate a heat-shock response upon Hsp90 induction [209]. However, in a SBMA mouse
model, overexpression of Hsp70 was able to improve the phenotype by reducing the levels
of the mutant AR [210]. This finding suggests that Hsp90 inhibitors would be able to
improve the health of neurons expressing mutant AR by both Hsp90 inhibition and
concurrent Hsp70 induction.
Perhaps the best-known polyQ disease is Huntington’s disease, characterized by the
aggregation of the multi-functional huntingtin protein. Similar to the other polyglutamine-
expansion diseases, increasing cellular Hsp70 and Hsp40 levels limited abnormal huntingtin
aggregation [211]. Inhibition of Hsp90 and Hsp70 also reduced aggregation of huntingtin
[83,212,213], which was recently confirmed as an Hsp90 client [214]. Interestingly,
huntingtin degradation is also regulated by CHIP [215,216]. Increasing the levels of CHIP
reduced both huntingtin aggregation and aggregation-dependent apoptosis [201]. Similar to
many other chaperone-dependent neurodegenerative diseases we’ve discussed, Hsc70 is
commonly observed associated with insoluble huntingtin cellular and brain aggregates
[217]. In a Saccharomyces cerevisae model of huntingtin aggregation other heat shock
proteins including Hsp26 and Hsp104 interacted with huntigntin [218]. Additionally, BAG1,
the same protein that influences tau fate through Hsc70 binding, may be playing a similar
role in determining the aggregation fate of huntingtin [219-224].
All of these results suggest that chaperones play critical roles in facilitating the accumulation
of mutated proteins in polyglutamine expansion diseases. The possible roles of Hsp70 and
Hsp90 in this disease system are strikingly similar to their suspected roles in facilitating
tauopathy and other neurodegenerative diseases. However, while Hsp90 inhibition and
increased Hsp70 expression have shown promise in alleviating toxic pathology of the
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polyglutamine diseases in both cellular and animal models, their effectiveness as therapeutic
strategies awaits validation in clinical trials.
Conclusions
As reviewed here, the Hsp90 chaperone network likely facilitates many proteinopathic
neurodegenerative diseases. Basal disease conditions dominated by constitutive Hsc70
expression favour the binding of aberrant clients to Hsc70. This client/Hsc70 complex then
presents the client to Hsp90 for (presumably) unsuccessful folding. Since Hsc70 is
commonly associated with insoluble client aggregates, we can surmise that, during disease
conditions, Hsc70 binding to aberrant clients favours client accumulation and aggregation.
Upon Hsp90 inhibition, however, two important changes take place. First, the folding
pathway of Hsp90 is eliminated as an option, shunting the flow of cycling clients toward
degradation pathways. Second, Hsp70 expression is greatly increased with the induced heat-
shock response. Experimental evidence shows that Hsp70 binding results in aberrant client
degradation, most likely by increasing the possibility that the Hsp70-client complex will be
ubiquitinated by CHIP and eventually degraded. While increasing Hsp70 expression alone
can decrease levels of aberrant client proteins, results from both cell and animal models of
neurodegeneration suggest that the greatest benefit comes from Hsp90 inhibition and the
combined actions of stopping client folding and increasing Hsp70 expression. Thus,
pharmacologic inhibition of Hsp90 and induction of a neuroprotective heat-shock response
have a two-pronged effect on aggregating neurodegenerative clients, in that the inhibition
breaks the “non-functional folding cycle” driven by Hsp90 and the subsequent induction of
HSPs increases the presence of the pro-degradation Hsp70 (Figures 1 and 2).
The role of the Hsp90 chaperone network machinery in the regulation of aberrant proteins
makes it a prime therapeutic target in treating the spectrum of neurodegenerative diseases
(Table 1). While Hsp90 inhibitors clearly show therapeutic potential in multiple animal
models expressing mutant aggregating proteins, it remains uncertain whether they will prove
similarly successful in the larger number of patients with idiopathic disease. Despite this,
mounting evidence suggests that most of these neurodegenerative models also benefit from
induction of the heat-shock response and/or increased expression of Hsp70 and the
subsequent degradation of problem proteins. This offers some hope that these processes may
be generalized to many proteinopathic neurodegenerative diseases. Much work remains to
fully elucidate the roles of Hsp90 network chaperones in neurodegenerative disease.
Experimental results from the last decade speak to the potential of chaperone manipulation,
specifically Hsp90 inhibition and up-regulation of Hsp70, as promising therapeutic
paradigms that may be applicable across a broad range of neurodegenerative disease.
Acknowledgments
G.C. is partly funded by 1U01 AG032969-01A1.
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Figure 1.
Inhibition of Hsp90 generates two distinct mechanisms both of which result in client protein
degradation and enhanced cell survival. Pathogenic Hsp90 “client” proteins are dependent
on Hsp90 for nascent folding and maintenance of structure. Upon Hsp90 inhibition, client
proteins, including those involved in disease lose stability and are degraded. Hsp90
inhibition also promotes the induction of other heat shock proteins through an HSF1
dependent mechanism. These HSPs can also promote clearance and block aggregation of
aberrant clients while enhancing cell survival under the “stressed” condition.
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Figure 2.
Protein folding pathways can prove to be detrimental when the chaperone folding machinery
fails to properly process an aberrant aggregation-prone client protein. Under the condition of
Hsp90 inhibition, Hsp90 is removed from the unproductive folding equation, disrupting this
pro-aggregation pathway. Also, inhibition of Hsp90 induces the HSPs, including Hsp70.
Increased levels of Hsp70 can facilitate a higher incident of interaction between client and
pro-degradation pathway. As an example, interaction of a client with an ubiquitin ligase
promotes proteasomal degradation of aberrant clients rather than accumulation and
aggregation.
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Carman et al. Page 27
Table 1
Shows Inhibition of Hsp90 and Hsp 70 which generates two distinct mechanisms both of which result in client protein degradation and enhanced cell
survival.
Protein Associated Neurodegenerative disease Benefit from Hsp70
elevation in vitro?Benefit from Hsp70
elevation in vivo?Benefit from Hsp90
inhibition in vitro?Benefit from Hsp90
inhibition in vivo?
Tau Tauopathies (AD, CBD, PSP, FTDP-17) Yes [61] Yes [61] Yes [62,90] Yes [62,90]
α-synuclein PD, DLB, MSA Yes [220] ? Yes[127,221] Yes [140]
LRRK2 PD Yes [138] ? Yes [139] ?
SOD1 ALS Yes [172-174] No [176] Yes [175] ?
TDP-43 ALS/FTD Yes [222] Yes [194] Yes [223] Yes [193]
Huntingtin HD Yes [211] No [212] Yes [83] Yes [212]
Androgen receptor SBMA Yes [106,206] Yes [210,224] Yes[207,209] Yes [207,208]
Ataxins SCA Yes [196] Yes [197,198] ? ?
J Alzheimers Dis Parkinsonism. Author manuscript; available in PMC 2014 September 23.
... Recent reviews have identified the upregulation of HSPs as therapeutic targets for the treatment of neurodegenerative diseases including Parkinson's disease and Alzheimer's disease (Carman et al., 2013;Kalmar et al., 2014;Schapira et al., 2014;Ciechanover and Kwon, 2017;Webster et al., 2017;Klaips et al., 2018). Neurodegenerative diseases are characterized by the progressive deterioration of structures within the central nervous system responsible for motor control, cognition, and autonomic function. ...
... HSPs function as chaperones to ensure appropriate cell function with distinct roles in the unfolded protein response, recognizing misfolded or mis-localized proteins that may be subsequently degraded by the proteasome, and are a key component of chaperone-mediated autophagy (Adachi et al., 2009;Stetler et al., 2010;Leak, 2014;Zarouchlioti et al., 2018). For their role in regulating protein homeostasis, HSP expression has been proposed as a therapeutic target for the treatment of these neurodegenerative diseases (Carman et al., 2013;Kalmar et al., 2014;Schapira et al., 2014;Ciechanover and Kwon, 2017;Webster et al., 2017;Klaips et al., 2018). ...
... Recent reviews have clearly identified the upregulation of HSPs as thermally activated therapeutic targets for the treatment of neurodegenerative diseases including Parkinson's and Alzheimer's (Carman et al., 2013;Kalmar et al., 2014;Schapira et al., 2014;Ciechanover and Kwon, 2017;Webster et al., 2017;Klaips et al., 2018). HSPs are a collective family of proteins, suffixed by their molecular weight (in kilodaltons; kDa), which are present in both constitutively expressed, and inducible isoforms across several intracellular tissue sites and in extracellular fluid following stress (Kampinga et al., 2009). ...
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Neurodegenerative diseases involve the progressive deterioration of structures within the central nervous system responsible for motor control, cognition, and autonomic function. Alzheimer’s disease, Parkinson’s disease, and motor neuron disease are among the most common neurodegenerative disease and have an increasing prevalence over the age of 50. Central in the pathophysiology of these neurodegenerative diseases is the loss of protein homeostasis, resulting in miss-folding and aggregation of damaged proteins. An element of the protein homeostasis network that prevents the dysregulation associated with neurodegeneration is the role of molecular chaperones. Heat shock proteins are chaperones that regulate the aggregation and disaggregation of proteins in intracellular and extracellular spaces, and evidence supports their protective effect against protein aggregation common to neurodegenerative diseases. Consequently, upregulation of heat shock proteins, such as HSP70, may be a target for therapeutic intervention for protection against neurodegeneration. A novel therapeutic intervention to increase the expression of heat shock protein may be found in heat therapy and/or heat acclimation. In healthy populations, these interventions have been shown to increase HSP expression. Elevated HSP may have central therapeutic effects, preventing or reducing the toxicity of protein aggregation, and/or peripherally by enhancing neuromuscular function. Broader physiological responses to heat therapy have also been identified and include improvements in muscle function, cerebral blood flow, and markers of metabolic health. These outcomes may also have a significant benefit for people with neurodegenerative disease. While there is limited research into body warming in patient populations, regular passive heating (sauna bathing) has been associated with a reduced risk of developing neurodegenerative disease. Therefore, the emerging evidence is compelling and warrants further investigation of the potential benefits of heat acclimation and passive heat therapy for sufferers of neurodegenerative diseases.
... Central in the pathophysiology of neurodegenerative diseases is the loss of protein homeostasis and the progressive loss of selective neurons. Protein homeostasis involves a complex system of protein synthesis, folding, disaggregation, and degradation that ensures the correct function of the human body and particularly the central nervous system [24]. Loss of protein homeostasis, due to protein mis-folding and aggregation of damaged proteins, is a hallmark of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases [25]. ...
... Recent reviews have clearly identified the upregulation of HSPs as thermally activated therapeutic targets for the treatment of neurodegenerative diseases including Parkinson's and Alzheimer's [24,26]. HSPs are a collective family of proteins, suffixed by their molecular weight (in kilodaltons; kDa), which are present in both constitutively expressed, and inducible isoforms across several intracellular tissue sites and in extracellular fluid following stress [27]. ...
... In addition, Hsp90 controls the stabilization and the misfolding of neurotoxic proteins and expedites tau pathology in AD (Sarah Kishinevsky et al. 2013). Suppressing Hsp90 d e c r e a s e s t h e l e v e l s o f S e r / T h r -m u t a t e d t a u , hyperphosphorylated tau, and the kinases, which are involved in continuous hyperphosphorylation (Jinwal et al. 2011). ...
... This suppression also expedites the binding of Hsp70 with aberrant proteins to produce a complex that is ubiquitinated by CHIP and damaged via proteolysis. Therefore, the suppression of Hsp90 raises the degradation of tau and maybe a prospective therapeutic approach for tau-based neurodegeneration in AD (Sarah Kishinevsky et al. 2013). ...
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The ubiquitin (Ub)-proteasome system (UPS) is considered as a central protein degradation system in all eukaryotes. The UPS comprises of several factors such as Ub and Ub-like molecules, Ub hydrolases, E3 Ub ligases, and the proteasome itself. Numerous studies have demonstrated that the dysfunction of UPS plays an essential role in the pathogenesis and progression of Alzheimer’s disease (AD). Furthermore, current evidence has suggested that the UPS components can be connected with the initial stage of AD that is characterized by synaptic dysfunction, and to the late phases of AD, marked by neurodegeneration. In AD patients, the accumulations of insoluble protein in the brain can be caused by overload or dysfunction of the UPS, or by conformational alterations in the protein substrates that prevent their degradation and recognition by the UPS. Synaptic dysfunction is also caused by defective proteolysis that has found in the initial stage in AD as the UPS is widely recognized to play a pivotal role in the regular activities of synapses. Conversely, its precise cause and pathogenesis are unclear. Presently accepted medicines for AD give symptomatic relief, though they are unable to stop the progression of the disease. Besides, the components of the cellular quality control system demonstrate a significant emphasis on the advancement of targeted and effective treatments for AD. In this review, we focus on the role of UPS in the pathogenesis of AD and highlight how the UPS-linked treatments influence in the management of AD.
... It is a molecular inhibitor of heat shock protein 90 (HSP90), a stabilizer of modified proteins in cancer and neurodegenerative disorders. In cellular and animal models of different neurodegenerative disorders, HSP90 inhibitors promote the degradation of pathogenic proteins (Carman et al., 2013). Epichaperomes are stable HSP90-centered chaperone complexes that incorporate proteins not physiologically associated with HSP90. ...
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Hexanucleotide expansion in C9orf72 has been related to several phenotypes to date, complicating the clinical recognition of these neurodegenerative disorders. An early diagnosis can improve the management of patients, promoting early administration of therapeutic supportive strategies. Here, we report known clinical presentations of C9orf72 -related neurodegenerative disorders, pointing out suggestive phenotypes that can benefit the genetic characterization of patients. Considering the high variability of C9orf72 -related disorder, frequent and rare manifestations are described, with detailed clinical, instrumental evaluation, and supportive therapeutical approaches. Furthermore, to improve the understanding of molecular pathways of the disease and potential therapeutical targets, a detailed description of the cellular mechanisms related to the pathological effect of C9orf72 is reported. New promising therapeutical strategies and ongoing studies are reported highlighting their molecular role in cellular pathological pathways of C9orf72 . These therapeutic approaches are particularly promising because they seem to stop the disease before neuronal damage. The knowledge of clinical and molecular features of C9orf72 -related neurodegenerative disorders improves the therapeutical application of known strategies and will lay the basis for the development of new potential therapies.
... The structure of the tau-HSP90 complex was identified by the Rüdiger lab to reveal the mechanism of tau regulation by this chaperone (Karagoz et al., 2014). The contribution and implications of several chaperones and co-chaperones in the folding of disease-associated proteins was also studied and reviewed in great detail (Bohush et al., 2019;Carman et al., 2013;Lackie et al., 2017;Lindberg et al., 2015) indicating the generalized importance of this mechanism for disease pathobiology. ...
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... Some Hsp90 inhibitors have been developed and tested especially for cancer therapy [16]. There are pathogenic conditions where aberrant Hsp90 client proteins are thought to have a crucial role, e.g., in many neurodegenerative and aggregation diseases; therefore, Hsp90 inhibitors are an interesting option in treating those diseases as well [17]. 17-AAG, a synthetic derivative of geldanamycin, has shown advantageous properties, such as anti-inflammatory effects in murine models of endotoxininduced uveitis, retinitis pigmentosa, and inherited retinal degeneration [18][19][20]. ...
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... Heat shock proteins (Hsps) are at the heart of proteostasis in eukaryotic cells, given their essential roles in protein folding and degradation pathways (Hartl et al. 2011). Hsps participate in damaged protein degradation and clearing either by the UPS or autophagy (Carman et al. 2013;Ciechanover and Kwon 2017;Witt 2013;Wyatt et al. 2013). Under normal physiological conditions, Hsp70 binding to client proteins in the early stages of protein folding controls the formation of proper protein folding and transport of mature proteins, while inhibiting aggregate formation. ...
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A monoclonal antibody to the microtubule-associated protein tau (tau) labeled some neurofibrillary tangles and plaque neurites, the two major locations of paired-helical filaments (PHF), in Alzheimer disease brain. The antibody also labeled isolated PHF that had been repeatedly washed with NaDodSO4. Dephosphorylation of the tissue sections with alkaline phosphatase prior to immunolabeling dramatically increased the number of tangles and plaques recognized by the antibody. The plaque core amyloid was not stained in either dephosphorylated or nondephosphorylated tissue sections. On immunoblots PHF polypeptides were labeled readily only when dephosphorylated. In contrast, a commercially available monoclonal antibody to a phosphorylated epitope of neurofilaments that labeled the tangles and the plaque neurites in tissue did not label any PHF polypeptides on immunoblots. The PHF polypeptides, labeled with the monoclonal antibody to tau, electrophoresed with those polypeptides recognized by antibodies to isolated PHF. The antibody to tau-labeled microtubules from normal human brains assembled in vitro but identically treated Alzheimer brain preparations had to be dephosphorylated to be completely recognized by this antibody. These findings suggest that tau in Alzheimer brain is an abnormally phosphorylated protein component of PHF.
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Eighty-three brains obtained at autopsy from nondemented and demented individuals were examined for extracellular amyloid deposits and intraneuronal neurofibrillary changes. The distribution pattern and packing density of amyloid deposits turned out to be of limited significance for differentiation of neuropathological stages. Neurofibrillary changes occurred in the form of neuritic plaques, neurofibrillary tangles and neuropil threads. The distribution of neuritic plaques varied widely not only within architectonic units but also from one individual to another. Neurofibrillary tangles and neuropil threads, in contrast, exhibited a characteristic distribution pattern permitting the differentiation of six stages. The first two stages were characterized by an either mild or severe alteration of the transentorhinal layer Pre-alpha (transentorhinal stages I-II). The two forms of limbic stages (stages III-IV) were marked by a conspicuous affection of layer Pre-alpha in both transentorhinal region and proper entorhinal cortex. In addition, there was mild involvement of the first Ammon's horn sector. The hallmark of the two isocortical stages (stages V-VI) was the destruction of virtually all isocortical association areas. The investigation showed that recognition of the six stages required qualitative evaluation of only a few key preparations.
Article
AMYOTROPHIC lateral sclerosis (ALS) is a degenerative disorder of motor neurons in the cortex, brainstem and spinal cord1,2. Its cause is unknown and it is uniformly fatal, typically within five years3. About 10% of cases are inherited as an autosomal dominant trait, with high penetrance after the sixth decade4,5. In most instances, sporadic and autosomal dominant familial ALS (FALS) are clinically similar4,6,7. We have previously shown that in some but not all FALS pedigrees the disease is linked to a genetic defect on chromosome 21q (refs 8, 9). Here we report tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O2.- to O2 and H2O2 (ref. 10). Given this linkage and the potential role of free radical toxicity in other neurodenegerative disorders11, we investigated SOD1 as a candidate gene in FALS. We identified 11 different SOD1 missense mutations in 13 different FALS families.
Article
Neurodegenerative diseases caused by abnormal accumulation of the microtubule associated protein tau (MAPT, tau) are collectively called tauopathies. The most devastating tau related disorder is Alzheimer's disease (AD). Molecular chaperones such as heat shock proteins (Hsp) have emerged as critical regulators of tau stability. Several studies from our group and others have shown that the chaperone network can be targeted for the development of therapeutic strategies for AD and other neurodegenerative diseases. Here we will discuss a recent paper and current work from our laboratory where we have manipulated the ATPase activity of the 70-kDa heat shock protein (Hsp70) to regulate tau turnover. A high-throughput screening assay revealed several compounds that activated or inhibited Hsp70's ATPase activity. Inhibitors dramatically and rapidly reduced tau levels, whereas activators stabilized tau, both in cells and brain tissue. Moreover, increased levels of Hsp70 improved ATPase inhibitor efficacy, suggesting that therapies aimed at inducing Hsp70 levels followed by inhibition of its ATPase activity may be a very effective strategy to treat AD. These findings demonstrate that Hsp70 ATPase activity can be targeted to modify the pathologies of AD and other tauopathies.
Article
A mutation in the alpha-synuclein gene has recently been linked to some cases of familial Parkinson's disease (PD). We characterized the expression of this presynaptic protein in the midbrain, striatum, and temporal cortex of control, PD, and dementia with Lewy bodies (DLB) brain. Control brain showed punctate pericellular immunostaining. PD brain demonstrated alpha-synuclein immunoreactivity in nigral Lewy bodies, pale bodies and abnormal neurites. Rare neuronal soma in PD brain were immunoreactive for alpha-synuclein. DLB cases demonstrated these findings as well as alpha-synuclein immunoreactivity in cortical Lewy bodies and CA2-3 neurites. These results suggest that, even in sporadic cases, there is an early and direct role for alpha-synuclein in the pathogenesis of PD and the neuropathologically related disorder DLB.