Pharmacological tuning of heat shock protein 70 modulates polyglutamine toxicity and aggregation.
Nine neurodegenerative disorders are caused by the abnormal expansion of polyglutamine (polyQ) regions within distinct proteins. Genetic and biochemical evidence has documented that the molecular chaperone, heat shock protein 70 (Hsp70), modulates polyQ toxicity and aggregation, yet it remains unclear how Hsp70 might be used as a potential therapeutic target in polyQ-related diseases. We have utilized a pair of membrane-permeable compounds that tune the activity of Hsp70 by either stimulating or by inhibiting its ATPase functions. Using these two pharmacological agents in both yeast and PC12 cell models of polyQ aggregation and toxicity, we were surprised to find that stimulating Hsp70 solubilized polyQ conformers and simultaneously exacerbated polyQ-mediated toxicity. By contrast, inhibiting Hsp70 ATPase activity protected against polyQ toxicity and promoted aggregation. These findings clarify the role of Hsp70 as a possible drug target in polyQ disorders and suggest that Hsp70 uses ATP hydrolysis to help partition polyQ proteins into structures with varying levels of proteotoxicity. Our results thus support an emerging concept in which certain kinds of polyQ aggregates may be protective, while more soluble polyQ species are toxic.
Boston Biomedical Research Institute, Watertown, MA 04272-2829, USA.
Sidhartha M
SM
Chafekar
Susanne
S
Wisén
Andrea D
AD
Thompson
AnaLisa
A
Echeverria
Gladis M
GM
Walter
Christopher G
CG
Evans
Leah N
LN
Makley
Jason E
JE
Gestwicki
Martin L
ML
Duennwald
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D018840:HSP70 Heat-Shock Proteins / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D016716:PC12 Cells; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D057165:Proteostasis Deficiencies / Q000188:drug therapy; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000254:growth & development; D012995:Solubility
D018840:HSP70 Heat-Shock Proteins; D010455:Peptides; C097188:polyglutamine; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases