CHIP suppresses polyglutamine aggregation and toxicity in vitro and in vivo

Victor M. Miller, Rick Nelson, Cynthia M. Gouvion, Aislinn Williams, Edgardo Rodriguez-Lebron, Scott Q. Harper, Beverly L. Davidson, Michael R. Rebagliati, Henry L. Paulson

Research output: Contribution to journalArticle

164 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)9152-9161
Number of pages10
JournalJournal of Neuroscience
Volume25
Issue number40
DOIs
StatePublished - Oct 5 2005
Externally publishedYes

Fingerprint

Huntington Disease
Neurodegenerative Diseases
Ubiquitin C
Proteins
Molecular Chaperones
HSP70 Heat-Shock Proteins
Aptitude
Zebrafish
Proteasome Endopeptidase Complex
Mutant Proteins
Ligases
Ubiquitin
Quality Control
Solubility
Transgenic Mice
In Vitro Techniques
polyglutamine
Phenotype
Neurons
Cell Line

Keywords

  • CHIP
  • Molecular chaperones
  • Neurodegeneration
  • polyQ
  • Proteasome
  • Zebrafish

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Miller, V. M., Nelson, R., Gouvion, C. M., Williams, A., Rodriguez-Lebron, E., Harper, S. Q., ... Paulson, H. L. (2005). CHIP suppresses polyglutamine aggregation and toxicity in vitro and in vivo. Journal of Neuroscience, 25(40), 9152-9161. https://doi.org/10.1523/JNEUROSCI.3001-05.2005

CHIP suppresses polyglutamine aggregation and toxicity in vitro and in vivo. / Miller, Victor M.; Nelson, Rick; Gouvion, Cynthia M.; Williams, Aislinn; Rodriguez-Lebron, Edgardo; Harper, Scott Q.; Davidson, Beverly L.; Rebagliati, Michael R.; Paulson, Henry L.

In: Journal of Neuroscience, Vol. 25, No. 40, 05.10.2005, p. 9152-9161.

Research output: Contribution to journalArticle

Miller, VM, Nelson, R, Gouvion, CM, Williams, A, Rodriguez-Lebron, E, Harper, SQ, Davidson, BL, Rebagliati, MR & Paulson, HL 2005, 'CHIP suppresses polyglutamine aggregation and toxicity in vitro and in vivo', Journal of Neuroscience, vol. 25, no. 40, pp. 9152-9161. https://doi.org/10.1523/JNEUROSCI.3001-05.2005
Miller VM, Nelson R, Gouvion CM, Williams A, Rodriguez-Lebron E, Harper SQ et al. CHIP suppresses polyglutamine aggregation and toxicity in vitro and in vivo. Journal of Neuroscience. 2005 Oct 5;25(40):9152-9161. https://doi.org/10.1523/JNEUROSCI.3001-05.2005
Miller, Victor M. ; Nelson, Rick ; Gouvion, Cynthia M. ; Williams, Aislinn ; Rodriguez-Lebron, Edgardo ; Harper, Scott Q. ; Davidson, Beverly L. ; Rebagliati, Michael R. ; Paulson, Henry L. / CHIP suppresses polyglutamine aggregation and toxicity in vitro and in vivo. In: Journal of Neuroscience. 2005 ; Vol. 25, No. 40. pp. 9152-9161.
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