Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation.

Abstract

We sought new strategies to reduce amounts of the polyglutamine androgen receptor (polyQ AR) and achieve benefits in models of spinobulbar muscular atrophy, a protein aggregation neurodegenerative disorder. Proteostasis of the polyQ AR is controlled by the heat shock protein 90 (Hsp90)- and Hsp70-based chaperone machinery, but mechanisms regulating the protein's turnover are incompletely understood. We demonstrate that overexpression of Hsp70 interacting protein (Hip), a co-chaperone that enhances binding of Hsp70 to its substrates, promotes client protein ubiquitination and polyQ AR clearance. Furthermore, we identify a small molecule that acts similarly to Hip by allosterically promoting Hsp70 binding to unfolded substrates. Like Hip, this synthetic co-chaperone enhances client protein ubiquitination and polyQ AR degradation. Both genetic and pharmacologic approaches targeting Hsp70 alleviate toxicity in a Drosophila model of spinobulbar muscular atrophy. These findings highlight the therapeutic potential of allosteric regulators of Hsp70 and provide new insights into the role of the chaperone machinery in protein quality control.

• Authors: Adrienne M Wang, Yoshinari Miyata, Susan Klinedinst, Hwei-Ming Peng, Jason P Chua, Tomoko Komiyama, Xiaokai Li, Yoshihiro Morishima, Diane E Merry, William B Pratt, Yoichi Osawa, Catherine A Collins, Jason E Gestwicki, Andrew P Lieberman
• Journal: Nature chemical biology (Nat Chem Biol) Vol. 9 Issue 2 Pg. 112-8 (Feb 2013) ISSN: 1552-4469 [Electronic] United States
• PMID: 23222885 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• HSP70 Heat-Shock Proteins
• Molecular Chaperones
• Neurotoxins
• Peptides
• Proteins
• Pyridines
• Receptors, Androgen
• Thiazoles
• N-(3-pyridylmethyl)adriamycin
• polyglutamine
• Doxorubicin
• MKT 077

Topics

• Animals
• Dose-Response Relationship, Drug
• Doxorubicin (analogs & derivatives, pharmacology)
• Drosophila
• Female
• HEK293 Cells
• HSP70 Heat-Shock Proteins (metabolism)
• HeLa Cells
• Humans
• Inhibitory Concentration 50
• Models, Chemical
• Molecular Chaperones (chemistry)
• Muscular Disorders, Atrophic (metabolism)
• Neurotoxins (chemistry)
• PC12 Cells
• Peptides (chemistry)
• Protein Structure, Tertiary
• Proteins (chemistry)
• Pyridines (pharmacology)
• Rats
• Receptors, Androgen (chemistry, metabolism)
• Thiazoles (pharmacology)
• Ubiquitination