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This article is part of the supplement: Proceedings of the 2011 International Conference on Molecular Neurodegeneration

Open Access Lecture presentation

Novel circuitry and molecular pathogenic mechanisms in Huntington's disease

X William Yang

  • Correspondence: X William Yang

Author Affiliations

Center for Neurobehavioral Genetics, Semel Institute, Department of Psychiatry & Biobehavioral Studies, David Geffen School of Medicine at UCLA, LA, California, USA

Molecular Neurodegeneration 2012, 7(Suppl 1):L18  doi:10.1186/1750-1326-7-S1-L18


The electronic version of this article is the complete one and can be found online at: http://www.molecularneurodegeneration.com/content/7/S1/L18


Published:7 February 2012

© 2012 Yang; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background

Huntington's disease (HD) is one of the most common inherited neurodegenerative disorders and is characterized clinically by the mid-age onset of progressive motor, cognitive and psychiatric deficits.

Methods

HD is caused by a CAG repeat expansion encoding an expanded glutamine repeat near the N-terminus of the huntingtin protein. How mutant huntingtin (mhtt) causes progressive and selective degeneration of striatal and cortical neurons, leading to symptoms of HD, remains unclear. In this presentation, I will describe a novel reductionist approach to use Cre/LoxP conditional Bacterial Artificial Chromosome (BAC) transgenic mouse models expressing full-length mhtt to dissect circuitry and molecular pathogenic mechanisms in HD.

Results

Our study defines the distinct but synergistic roles of cortical and striatal projection neurons in HD pathogenesis, and uncovers novel evidence for HD being a non-cell-autonomous disease. Finally, we show that phosphorylation of a small mhtt N-terminus domain can act as a molecular switch to suppress HD pathogenesis in vivo.

Conclusion

Together, our studies provide novel mechanistic and therapeutic insights for HD.