CHIP suppresses polyglutamine aggregation and toxicity in vitro and in vivo

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

doi:10.1523/JNEUROSCI.3001-05.2005

Back

CHIP suppresses polyglutamine aggregation and toxicity in vitro and in vivo

Journal article

Open access

Peer reviewed

CHIP suppresses polyglutamine aggregation and toxicity in vitro and in vivo

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

The Journal of neuroscience, Vol.25(40), pp.9152-9161

10/05/2005

DOI: 10.1523/JNEUROSCI.3001-05.2005

PMCID: PMC6725774

PMID: 16207874

Files and links (1)

url

https://doi.org/10.1523/JNEUROSCI.3001-05.2005View

Published (Version of record) Open Access

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.

Embryo, Mammalian

Microtubule-Associated Proteins - metabolism

Peptides - genetics

Cercopithecus aethiops

Neurons - cytology

Cerebral Cortex - cytology

Peptides - metabolism

Transfection - methods

Huntington Disease - drug therapy

Neurons - drug effects

Disease Models, Animal

Green Fluorescent Proteins - metabolism

Blotting, Western - methods

Fluorescent Antibody Technique - methods

Cells, Cultured

Rats

Mice, Transgenic

Zebrafish

Ubiquitin-Protein Ligases - pharmacology

Animals

Green Fluorescent Proteins - biosynthesis

Embryo, Nonmammalian

Mice

Mutation

Radioimmunoassay - methods

In Vitro Techniques

Neural Inhibition - drug effects

Details

Title: Subtitle: CHIP suppresses polyglutamine aggregation and toxicity in vitro and in vivo
Creators: Victor M Miller - Department of Neurology, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242, USA
Rick F Nelson
Cynthia M Gouvion
Aislinn Williams
Edgardo Rodriguez-Lebron
Scott Q Harper
Beverly L Davidson
Michael R Rebagliati
Henry L Paulson
Resource Type: Journal article
Publication Details: The Journal of neuroscience, Vol.25(40), pp.9152-9161
Publisher: United States
DOI: 10.1523/JNEUROSCI.3001-05.2005
PMID: 16207874
PMCID: PMC6725774
ISSN: 0270-6474
eISSN: 1529-2401
Grant note: NS38712 / NINDS NIH HHS F30NS047872 / NINDS NIH HHS NS47535 / NINDS NIH HHS T32 GM08629 / NIGMS NIH HHS
Language: English
Date published: 10/05/2005
Academic Unit: Psychiatry; Microbiology and Immunology; Iowa Neuroscience Institute; Biology
Record Identifier: 9984066386602771

Metrics

32 Record Views

189 Times Cited - Web of Science

See more details