Human Molecular Genetics Advance Access originally published online on July 1, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 16 2021-2030
DOI: 10.1093/hmg/ddg218
© 2003 Oxford University Press
Abnormal association of mutant huntingtin with synaptic vesicles inhibits glutamate release
1Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA and 2Department of Anatomy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China
Received April 16, 2003; Revised June 16, 2003; Accepted June 23, 2003
In Huntington disease (HD), polyglutamine expansion causes the disease protein huntingtin to aggregate and accumulate in the nucleus and cytoplasm. The cytoplasmic huntingtin aggregates are found in axonal terminals and electrophysiological studies show that mutant huntingtin affects synaptic neurotransmission. However, the biochemical basis for huntingtin-mediated synaptic dysfunction is unclear. Using electron microscopy on sections of HD mouse brains, we found that axonal terminals containing huntingtin aggregates often had fewer synaptic vesicles than did normal axonal terminals. Subcellular fractionation and electron microscopy revealed that mutant huntingtin is co-localized with huntingtin-associated protein-1 (HAP1) in axonal terminals in the brains of HD transgenic mice. Mutant huntingtin binds more tightly to synaptic vesicles than does normal huntingtin, and it decreases the association of HAP1 with synaptic vesicles in HD mouse brains. Brain slices from HD transgenic mice that had axonal aggregates showed a significant decrease in [3H]glutamate release, suggesting that neurotransmitter release from synaptic vesicles was impaired. Taken together, these findings suggest that mutant huntingtin has an abnormal association with synaptic vesicles and this association impairs synaptic function.
* To whom correspondence should be addressed at: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA. Tel: +1 4047273290; Fax: +1 4047273949; Email: xiaoli{at}genetics.emory.edu
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