Journal
JOURNAL OF NEUROSCIENCE
Volume 25, Issue 40, Pages 9152-9161Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3001-05.2005
Keywords
polyQ; CHIP; zebrafish; neurodegeneration; proteasome; molecular chaperones
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Funding
- NIGMS NIH HHS [T32 GM08629, T32 GM008629] Funding Source: Medline
- NINDS NIH HHS [NS38712, F30NS047872, NS47535, R01 NS038712, R01 NS047535, F30 NS047872] Funding Source: Medline
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Huntington's disease (HD) and other polyglutamine (polyQ) neurodegenerative diseases are characterized by neuronal accumulation of the disease protein, suggesting that the cellular ability to handle abnormal proteins is compromised. As both a cochaperone and ubiquitin ligase, the C-terminal Hsp70 (heat shock protein 70)-interacting protein ( CHIP) links the two major arms of protein quality control, molecular chaperones, and the ubiquitin-proteasome system. Here, we demonstrate that CHIP suppresses polyQ aggregation and toxicity in transfected cell lines, primary neurons, and a novel zebrafish model of disease. Suppression by CHIP requires its cochaperone function, suggesting that CHIP acts to facilitate the solubility of mutant polyQ proteins through its interactions with chaperones. Conversely, HD transgenic mice that are haploinsufficient for CHIP display a markedly accelerated disease phenotype. We conclude that CHIP is a critical mediator of the neuronal response to misfolded polyQ protein and represents a potential therapeutic target in this important class of neurodegenerative diseases.
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