Huntington's disease (HD) is one of the most common dominantly inherited neurodegenerative disorders affecting 30,000 patients in the US with another 150,000 at risk. HD is characterized by motor, cognitive and psychiatric symptoms that often progress and result in the patient's death in about 10-20 years after disease onset. HD is caused by a polylgutamine repeat expansion in mutant Huntington, resulting in the relentless progression of neurodegeneration primarily targeting the striatal neurons but also affecting the cortical neurons. Currently, there is no treatment or cure for HD. Since mutant huntingtin (mhtt) is widely expressed in the brain and in the body but neuro degeneration in HD primarily targets the striatal and cortical neurons, a critical yet unanswered question in HD is how does the widely distributed mhtt cause such selective patterns of neuro degeneration? To address this question, we first will ask where mhtt expression is critical for disease pathogenesis. Using a novel series of HD mouse models that can express mhtt or its toxic fragments in different types of cells in the brain, we discovered that mhtt fragments can induce not only the intrinsic toxicities to the neurons in which it is expressed but also toxic interactions between different types of neurons. Furthermore, we found that switching off mhtt expression in the cortical neurons results in a significant but partial rescue of both the behavioral deficits and striatal toxicities in HD mice. These exciting findings underscore the need to study whether and how the cortical and striatal neurons may act together to elicit HD. We designed the following aims to address this critical question:
Aim 1. Is mhtt expression in the striatum necessary for HD pathogenesis? Aim 2. Can switching off full length mhtt expression in both the cortex and striatum synergically reduce key disease phenotypes in HD mice? Aim 3. Can switching of full length mhtt only in the cortical pyramidal neurons and striatal medium spiny neurons be sufficient to induce key aspects of HD phenotypes in vivo? The completion of our study may reveal whether mhtt exert synergistic toxic effects from within two types of neurons (i.e. the striatal and cortical neurons) to elicit the major disease phenotypes in HD. Our study may support the molecular dissection of HD pathogenic mechanisms in these two cell types, and may further inform us on the optimal strategies of local delivery of mhtt reducing therapeutics (i.e. RNA interference, antisense oligonucleotides or intrabodies).

Public Health Relevance

Huntington's disease (HD) is one of the most common dominantly inherited neurodegenerative disorders affecting 30,000 patients in the US and another 150,000 at risk. Currently, HD is not treatable or curable, and the patients invariably suffer from the motor, cognitive and psychiatric symptoms that often relentlessly progress toward an eventual bedridden state and death about 10-20 years after the disease onset. Our proposed study is aimed at identifying the critical neuronal cell types targeted by toxic mhtt to elicit the key disease phenotypes in HD. Hence, our study may provide the crucial cellular targets from which we can dissect the molecular pathogenic mechanisms and to deliver HD therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS049501-10
Application #
8585123
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Sutherland, Margaret L
Project Start
2004-09-01
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
10
Fiscal Year
2014
Total Cost
$297,125
Indirect Cost
$104,187
Name
University of California Los Angeles
Department
None
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Haustein, Martin D; Kracun, Sebastian; Lu, Xiao-Hong et al. (2014) Conditions and constraints for astrocyte calcium signaling in the hippocampal mossy fiber pathway. Neuron 82:413-29
Wang, Nan; Gray, Michelle; Lu, Xiao-Hong et al. (2014) Neuronal targets for reducing mutant huntingtin expression to ameliorate disease in a mouse model of Huntington's disease. Nat Med 20:536-41
Southwell, Amber L; Warby, Simon C; Carroll, Jeffrey B et al. (2013) A fully humanized transgenic mouse model of Huntington disease. Hum Mol Genet 22:18-34
Lee, C Y Daniel; Cantle, Jeffrey P; Yang, X William (2013) Genetic manipulations of mutant huntingtin in mice: new insights into Huntington's disease pathogenesis. FEBS J 280:4382-94
Wilburn, Brian; Rudnicki, Dobrila D; Zhao, Jing et al. (2011) An antisense CAG repeat transcript at JPH3 locus mediates expanded polyglutamine protein toxicity in Huntington's disease-like 2 mice. Neuron 70:427-40
Andre, Veronique M; Cepeda, Carlos; Fisher, Yvette E et al. (2011) Differential electrophysiological changes in striatal output neurons in Huntington's disease. J Neurosci 31:1170-82
Tao, Jifang; Wu, Hao; Lin, Quan et al. (2011) Deletion of astroglial Dicer causes non-cell-autonomous neuronal dysfunction and degeneration. J Neurosci 31:8306-19
Pouladi, Mahmoud A; Xie, Yuanyun; Skotte, Niels Henning et al. (2010) Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression. Hum Mol Genet 19:1528-38
Graham, Rona K; Deng, Yu; Carroll, Jeffery et al. (2010) Cleavage at the 586 amino acid caspase-6 site in mutant huntingtin influences caspase-6 activation in vivo. J Neurosci 30:15019-29
Gu, Xiaofeng; Greiner, Erin R; Mishra, Rakesh et al. (2009) Serines 13 and 16 are critical determinants of full-length human mutant huntingtin induced disease pathogenesis in HD mice. Neuron 64:828-40

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