Journal article
In vivo suppression of polyglutamine neurotoxicity by C-terminus of Hsp70-interacting protein (CHIP) supports an aggregation model of pathogenesis
Neurobiology of disease, Vol.33(3), pp.342-353
03/2009
DOI: 10.1016/j.nbd.2008.10.016
PMCID: PMC2662361
PMID: 19084066
Abstract
Perturbations in neuronal protein homeostasis likely contribute to disease pathogenesis in polyglutamine (polyQ) neurodegenerative disorders. Here we provide evidence that the co-chaperone and ubiquitin ligase, CHIP (C-terminus of Hsp70-interacting protein), is a central component to the homeostatic mechanisms countering toxic polyQ proteins in the brain. Genetic reduction or elimination of CHIP accelerates disease in transgenic mice expressing polyQ-expanded ataxin-3, the disease protein in Spinocerebellar Ataxia Type 3 (SCA3). In parallel, CHIP reduction markedly increases the level of ataxin-3 microaggregates, which partition in the soluble fraction of brain lysates yet are resistant to dissociation with denaturing detergent, and which precede the appearance of inclusions. The level of microaggregates in the CNS, but not of ataxin-3 monomer, correlates with disease severity. Additional cell-based studies suggest that either of two quality control ubiquitin ligases, CHIP or E4B, can reduce steady state levels of expanded, but not wild-type, ataxin-3. Our results support an aggregation model of polyQ disease pathogenesis in which ataxin-3 microaggregates are a neurotoxic species, and suggest that enhancing CHIP activity is a possible route to therapy for SCA3 and other polyQ diseases.
Details
- Title: Subtitle
- In vivo suppression of polyglutamine neurotoxicity by C-terminus of Hsp70-interacting protein (CHIP) supports an aggregation model of pathogenesis
- Creators
- Aislinn J Williams - Graduate Program in Neuroscience and Medical Scientist Training Program, University of Iowa, 2206 MERF, Iowa City, IA 52242, USA. aiwillia@umich.eduTina M KnutsonVeronica F Colomer GouldHenry L Paulson
- Resource Type
- Journal article
- Publication Details
- Neurobiology of disease, Vol.33(3), pp.342-353
- DOI
- 10.1016/j.nbd.2008.10.016
- PMID
- 19084066
- PMCID
- PMC2662361
- NLM abbreviation
- Neurobiol Dis
- ISSN
- 0969-9961
- eISSN
- 1095-953X
- Publisher
- United States
- Grant note
- NS38712 / NINDS NIH HHS R01 NS038712-11 / NINDS NIH HHS NS056609 / NINDS NIH HHS F31 NS056609 / NINDS NIH HHS T32 GM007337 / NIGMS NIH HHS R01 NS038712 / NINDS NIH HHS F31 NS056609-02 / NINDS NIH HHS R01 NS038712-10 / NINDS NIH HHS
- Language
- English
- Date published
- 03/2009
- Academic Unit
- Psychiatry; Iowa Neuroscience Institute
- Record Identifier
- 9984065833602771
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