Targeting Hsp70 facilitated protein quality control for treatment of polyglutamine diseases.

Targeting Hsp70 facilitated protein quality control for treatment of polyglutamine diseases.

Publication date: Sep 24, 2019

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.

Davis, A.K., Pratt, W.B., Lieberman, A.P., and Osawa, Y. Targeting Hsp70 facilitated protein quality control for treatment of polyglutamine diseases. 06691. 2019 Cell Mol Life Sci.

Concepts Keywords
Chaperone Chaperone machinery
Chaperones Branches of biology
Heat Shock Proteins
Homeostasis Heat shock proteins
Hsp70 Molecular chaperones
Hsp90 Neurological disorders
Misfolding Heat shock response
Mutant Neurodegeneration
Neurodegenerative Disorders Hsp90
PolyQ Hsp70
Sci PolyQ

Semantics

Type Source Name
disease DOID Spinocerebellar ataxia
disease DOID Spinal bulbar muscular atrophy
disease DOID Huntington disease
disease MESH Huntington disease
gene UNIPROT RXFP2
disease MESH development
disease MESH shock
disease MESH neurodegenerative disorders

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