Targeting Hsp70 facilitated protein quality control for treatment of polyglutamine diseases

Davis, Amanda; Pratt, William B.; Lieberman, Andrew P.; Osawa, Yoichi

doi:10.1007/s00018-019-03302-2

Cited by 27 publications

(35 citation statements)

References 194 publications

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“…Its closest human ortholog is the constitutively expressed, heat shock protein family A member 8 (HSPA8; Takayama et al, 1999 ). Alongside other HSP70 members, its primary role is that of an ATP-dependent chaperone for unfolded proteins in protein quality control ( Yamamoto et al, 2010 ; Grove et al, 2011 ; Goodwin et al, 2014 ; Li et al, 2017 ; Sopha et al, 2012 ; Robert et al, 2019 ; Loeffler, 2019 ; Abildgaard et al, 2020 ; Davis et al, 2020 ; Faust and Rosenzweig, 2020 ). HSPA8 is a part of the ubiquitin-proteasome degradation system and is also involved in chaperone-mediated autophagy ( Robert et al, 2019 ; Loeffler, 2019 ; Stricher et al, 2013 ; Kampinga and Bergink, 2016 ).…”

Section: Resultsmentioning

confidence: 99%

“…It is intriguing that knockdown of Hsc70-4 reduces toxicity from pathogenic ataxin-3. As mentioned above, heat shock proteins generally work to improve toxicity from aggregated proteins ( Davis et al, 2020 ; Warrick et al, 1999 ; Duncan et al, 2015 ; Evans et al, 2010 ; Thiruvalluvan et al, 2020 ; Chan et al, 2000 ; Vossfeldt et al, 2012 ; Kampinga and Bergink, 2016 ). Hsc70-4 may act in a context-, protein-, and disease-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

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Ubiquitin-interacting motifs of ataxin-3 regulate its polyglutamine toxicity through Hsc70-4-dependent aggregation

Johnson

Ranxhi

Libohova

et al. 2020

eLife

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Spinocerebellar ataxia type 3 (SCA3) belongs to the family of polyglutamine neurodegenerations. Each disorder stems from the abnormal lengthening of a glutamine repeat in a different protein. Although caused by a similar mutation, polyglutamine disorders are distinct, implicating non-polyglutamine regions of disease proteins as regulators of pathogenesis. SCA3 is caused by polyglutamine expansion in ataxin-3. To determine the role of ataxin-3’s non-polyglutamine domains in disease, we utilized a new, allelic series of Drosophila melanogaster. We found that ataxin-3 pathogenicity is saliently controlled by polyglutamine-adjacent ubiquitin-interacting motifs (UIMs) that enhance aggregation and toxicity. UIMs function by interacting with the heat shock protein, Hsc70-4, whose reduction diminishes ataxin-3 toxicity in a UIM-dependent manner. Hsc70-4 also enhances pathogenicity of other polyglutamine proteins. Our studies provide a unique insight into the impact of ataxin-3 domains in SCA3, identify Hsc70-4 as a SCA3 enhancer, and indicate pleiotropic effects from HSP70 chaperones, which are generally thought to suppress polyglutamine degeneration.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ubiquitin-interacting motifs of ataxin-3 regulate its polyglutamine toxicity through Hsc70-4-dependent aggregation

Johnson

Ranxhi

Libohova

et al. 2020

eLife

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“…It is tempting to speculate that our findings suggest a potential functional therapeutic for human neurodegenerative disease. Engineered chaperone overexpression to combat diseases of protein misfolding is fraught with nonspecific and collateral effects due to the key roles chaperones play in all cellular biology ( 61 , 62 , 63 ). It is possible that further investigations into using the Hsp110 IDR peptide alone or attached to an inert protein scaffold may yield a deliverable tool that would block or delay fibril and plaque formation in several amyloidogenic disorders.…”

Section: Discussionmentioning

confidence: 99%

Suppression of aggregate and amyloid formation by a novel intrinsically disordered region in metazoan Hsp110 chaperones

Yakubu

Morano

2021

Journal of Biological Chemistry

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Molecular chaperones maintain proteostasis by ensuring the proper folding of polypeptides. Loss of proteostasis has been linked to numerous neurodegenerative disorders including Alzheimer's, Parkinson's, and Huntington's disease. Hsp110 is related to the canonical Hsp70 class of protein-folding molecular chaperones and interacts with Hsp70 as a nucleotide exchange factor (NEF). In addition to its NEF activity, Hsp110 possesses an Hsp70-like substrate-binding domain (SBD) whose biological roles remain undefined. Previous work in Drosophila melanogaster has implicated the sole Hsp110 gene (Hsc70cb) in proteinopathic neurodegeneration. We hypothesize that in addition to its role as an Hsp70 NEF, Drosophila Hsp110 may function as a protective protein "holdase," preventing the aggregation of unfolded polypeptides via the SBD-β subdomain. We demonstrate for the first time that Drosophila Hsp110 effectively prevents aggregation of the model substrate citrate synthase. We also report the discovery of a redundant and heretofore unknown potent holdase capacity in a 138-amino-acid region of Hsp110 carboxyl terminal to both SBD-β and SBD-α (henceforth called the C-terminal extension). This sequence is highly conserved in metazoan Hsp110 genes, completely absent from fungal representatives, and is computationally predicted to contain an intrinsically disordered region (IDR). We demonstrate that this IDR sequence within the human Hsp110s, Apg-1 and Hsp105α, inhibits the formation of amyloid Aβ-42 and α-synuclein fibrils in vitro but cannot mediate fibril disassembly. Together these findings establish capacity for metazoan Hsp110 chaperones to suppress both general protein aggregation and amyloidogenesis, raising the possibility of exploitation of this IDR for therapeutic benefit.

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“…We first assayed in our adult glial HD model the potency of a set of chaperones to rescue the pathology when overexpressed, as it is the case in several models of polyQ diseases targeting neuronal cells [ 27 ]. Overexpression of two chaperones, Hsc70Cb and HSP68, and of the DNAJ1 co-chaperone robustly increased the longevity of the HD flies while overexpression of the human HSPA4L chaperone was inefficient ( Figure 2 a).…”

Section: Resultsmentioning

confidence: 99%

Genetic Screen in Adult Drosophila Reveals That dCBP Depletion in Glial Cells Mitigates Huntington Disease Pathology through a Foxo-Dependent Pathway

Martin

Heidari

Monnier

et al. 2021

IJMS

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Huntington’s disease (HD) is a progressive and fatal autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the first exon of the huntingtin gene (HTT). In spite of considerable efforts, there is currently no treatment to stop or delay the disease. Although HTT is expressed ubiquitously, most of our knowledge has been obtained on neurons. More recently, the impact of mutant huntingtin (mHTT) on other cell types, including glial cells, has received growing interest. It is currently unclear whether new pathological pathways could be identified in these cells compared to neurons. To address this question, we performed an in vivo screen for modifiers of mutant huntingtin (HTT-548-128Q) induced pathology in Drosophila adult glial cells and identified several putative therapeutic targets. Among them, we discovered that partial nej/dCBP depletion in these cells was protective, as revealed by strongly increased lifespan and restored locomotor activity. Thus, dCBP promotes the HD pathology in glial cells, in contrast to previous opposite findings in neurons. Further investigations implicated the transcriptional activator Foxo as a critical downstream player in this glial protective pathway. Our data suggest that combinatorial approaches combined to specific tissue targeting may be required to uncover efficient therapies in HD.

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Targeting Hsp70 facilitated protein quality control for treatment of polyglutamine diseases

Cited by 27 publications

References 194 publications

Ubiquitin-interacting motifs of ataxin-3 regulate its polyglutamine toxicity through Hsc70-4-dependent aggregation

Ubiquitin-interacting motifs of ataxin-3 regulate its polyglutamine toxicity through Hsc70-4-dependent aggregation

Suppression of aggregate and amyloid formation by a novel intrinsically disordered region in metazoan Hsp110 chaperones

Genetic Screen in Adult Drosophila Reveals That dCBP Depletion in Glial Cells Mitigates Huntington Disease Pathology through a Foxo-Dependent Pathway

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