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Author Notes:

Correspondence to Shihua Li: shihual@genetics.emory.edu; or Xiao-Jiang Li: xli2@emory.edu

We thank Duc M. Duong and Nicholas T. Seyfried at ENNCF (Emory Neuroscience National Institute of Neurological Disorders and Stroke [NINDS] Core Facility) proteomics core at Emory University for MS analysis, Heju Zhang at the Transgenic Mouse/Gene Targeting Core Facility at Emory University for generating transgenic mice, Dr. William Yang for providing the plasmid for expressing N-terminal htt, and Cheryl Strauss for critical reading of this manuscript.

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Research Funding:

The work was supported by National Institutes of Health grants (AG19206 and NS041449 to X.-J. Li, AG031153 and NS0405016 to S. Li, and NS057255 to S.P. Yu), and Q.Q. Xu was supported in part by the graduate program at Tongji Medical College, Huazhong University of Science and Technology.

This research project was supported in part by the Proteomics Core of the Emory Neuroscience NINDS Core Facilities grant (P30NS055077) and the State Key Laboratory of Molecular Developmental Biology, China.

Synaptic mutant huntingtin inhibits synapsin-1 phosphorylation and causes neurological symptoms

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Journal Title:

Journal of Cell Biology

Volume:

Volume 202, Number 7

Publisher:

, Pages 1123-1138

Type of Work:

Article | Final Publisher PDF

Abstract:

Many genetic mouse models of Huntington’s disease (HD) have established that mutant huntingtin (htt) accumulates in various subcellular regions to affect a variety of cellular functions, but whether and how synaptic mutant htt directly mediates HD neuropathology remains to be determined. We generated transgenic mice that selectively express mutant htt in the presynaptic terminals. Although it was not overexpressed, synaptic mutant htt caused age-dependent neurological symptoms and early death in mice as well as defects in synaptic neurotransmitter release. Mass spectrometry analysis of synaptic fractions and immunoprecipitation of synapsin-1 from HD CAG150 knockin mouse brains revealed that mutant htt binds to synapsin-1, a protein whose phosphorylation is critical for neurotransmitter release. We found that polyglutamine-expanded exon1 htt binds to the C-terminal region of synapsin-1 to reduce synapsin-1 phosphorylation. Our findings point to a critical role for synaptic htt in the neurological symptoms of HD, providing a new therapeutic target.

Copyright information:

© 2013 Xu et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License (http://creativecommons.org/licenses/by-nc-sa/3.0/).

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