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Targeting Hsp70 facilitated protein quality control for treatment of polyglutamine diseases

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Abstract

The polyglutamine (polyQ) diseases are a group of nine fatal, adult-onset neurodegenerative disorders characterized by the misfolding and aggregation of mutant proteins containing toxic expansions of CAG/polyQ tracts. The heat shock protein 90 and 70 (Hsp90/Hsp70) chaperone machinery is a key component of cellular protein quality control, playing a role in the regulation of folding, aggregation, and degradation of polyQ proteins. The ability of Hsp70 to facilitate disaggregation and degradation of misfolded proteins makes it an attractive therapeutic target in polyQ diseases. Genetic studies have demonstrated that manipulation of Hsp70 and related co-chaperones can enhance the disaggregation and/or degradation of misfolded proteins in models of polyQ disease. Therefore, the development of small molecules that enhance Hsp70 activity is of great interest. However, it is still unclear if currently available Hsp70 modulators can selectively enhance disaggregation or degradation of misfolded proteins without perturbing other Hsp70 functions essential for cellular homeostasis. This review discusses the multifaceted role of Hsp70 in protein quality control and the opportunities and challenges Hsp70 poses as a potential therapeutic target in polyQ disease.

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Abbreviations

AC:

Azure C

AR:

Androgen receptor

ATXN:

Ataxin

BAG:

Bcl-2 associated athanogene

CASA:

Chaperone-assisted selective autophagy

CHIP:

C-terminus of Hsp70 interacting protein

CMA:

Chaperone-mediated autophagy

dHMNII:

Distal hereditary motor neuropathy type II

DRPLA:

Dentatorubral pallidoluysian atrophy

eMI:

Endosomal microautophagy

GR:

Glucocorticoid receptor

HD:

Huntington’s disease

HIP:

Hsp70 interacting protein

HOP:

Hsp organizing protein

HSF1:

Heat shock factor 1

Hsp:

Heat shock protein

Hsp70:

Heat shock protein 70

Hsp90:

Heat chock protein 90

HspBP1:

Hsp70-binding protein 1

HSR:

Heat shock response

Htt:

Huntingtin

LAMP2A:

Lysosome associated membrane protein type 2A

LGMD1:

Limb-girdle muscular dystrophy type 1

MB:

Methylene blue

MTOC:

Microtubule organization center

NBD:

Nucleotide binding domain

NEF:

Nucleotide exchange factor

polyQ:

Polyglutamine

PR:

Progesterone receptor

SBD:

Substrate binding domain

SBMA:

Spinal bulbar muscular atrophy

SCA:

Spinocerebellar ataxia

sHsp:

Small heat shock protein

TFEB:

Transcriptional factor EB

TPR:

Tetratricopeptide repeat

UBQLN2:

Ubiquilin-2

UPS:

Ubiquitin proteasome system

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Acknowledgements

Work in the authors’ laboratories was supported by the National Institutes of Health (NS101030, NS055746 to YO and APL; GM077430 to YO; T32-GM007767 to AKD), and the PhRMA Foundation (Predoctoral Fellowship in Pharmacology/Toxicology to AKD). The authors are all participants in The University of Michigan Medical School’s Protein Folding Diseases Initiative.

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  1. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA

    Amanda K. Davis, William B. Pratt & Yoichi Osawa

  2. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA

    Andrew P. Lieberman

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Davis, A.K., Pratt, W.B., Lieberman, A.P. et al. Targeting Hsp70 facilitated protein quality control for treatment of polyglutamine diseases. Cell. Mol. Life Sci. 77, 977–996 (2020). https://doi.org/10.1007/s00018-019-03302-2

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