Huntington's disease (HD) is one of the most devastating human diseases known, affecting approximately 120,000 people in the USA. Despite extensive research there is currently no effective treatment for the disease. Our previous studies conducted in fibroblast, neuronal and C. elegans models of HD have shown that overexpression of ubiquilin (ubqln) reduces toxicity of mutant huntingtin (htt) proteins containing expanded polyglutamine repeats. The results suggest that modulation of ubqln expression might be an attractive target for treating HD. However, before such consideration, a necessary and important perquisite is to validate whether overexpression of ubqln can reduce HD-like symptoms in mouse models of the disease. To conduct such tests we have now obtained transgenic mice that overexpress human ubqln-1 throughout the brain, including the striatum and hippocampus. The mice are completely normal based on lifespan and behavioral assays. In an initial test we crossed our ubqln-1 transgenic mice with the R6/2 model of HD and found ubqln-1 overexpression almost completely restores a progressive decline in ubqln levels seen in the brains of R6/2 animals during late stages of the disease. Interestingly, ubqln-1 overexpression reduced htt protein aggregation and increased survival of R6/2 mice by 20%. Despite these alterations we found no significant difference in behavioral defects in the mice, which might be attributed to high expression and penetrance of the toxic R6/2 mutant htt exon- 1 transgenic fragment. It is important that we repeat the test with better models of HD. Two such models are the YAC128 and CAG knock-in mice, both of which express mutant full-length htt proteins at more physiological levels. These HD models have more attenuated HD symptoms over an extended period and should be better suited for our test. Therefore, in Aim 1 we will cross transgenic mice that overexpress human ubiquilin-1 with the YAC128 transgenic mice to evaluate whether ubiquilin-1 overexpression delays and/or prevents the time-course of development of neuropathology and disease symptoms in this model of HD.
Aim 2 is a repetition of Aim 1, but differs in that we will use the CAG200 knock-in mouse model of HD instead of the YAC128 mice. We will complement these animal studies with in vitro studies using cultured neurons isolated from the mice that should provide mechanistic into the mode of ubiquilin action in regulating htt toxicity. The results from this study will provide a critical tet of whether ubqln overexpression can delay or prevent HD symptoms. If validated the results could have high impact for HD as it would suggest efforts to find factors that modulate ubiquilin expression could be successfully used for treatment of HD. We describe the next logical steps of how this could be done.

Public Health Relevance

The research proposed here is to validate our hypothesis that an increase in ubiquilin-1 expression in mouse models of Huntington's disease will reduce symptoms and neuropathology associated with Huntington's disease. The research has important and direct implications for human health, because the research could lead to development of methods to regulate ubiquilin levels or its activity to treat Huntington's disease, a disease for which there is currently no available treatment.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Sutherland, Margaret L
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University of Maryland Baltimore
Anatomy/Cell Biology
Schools of Medicine
United States
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Safren, Nathaniel; Chang, Lydia; Dziki, Kristina M et al. (2015) Signature changes in ubiquilin expression in the R6/2 mouse model of Huntington's disease. Brain Res 1597:37-46