Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is caused by a pathological expansion of CAG repeats within the gene encoding for a 350 kD protein called huntingtin. This polyglutamine expansion within huntingtin is fundamental to the pathogenesis of HD, however the mechanisms by which this mutation causes the disease are unknown. One of the leading hypotheses of the etiology of HD is that mutant huntingtin directly or indirectly compromises mitochondrial function resulting in impairment of energy metabolism, increased oxidative damage and eventually neuronal death. Indeed, a marked reduction in the activity of mitochondrial complexes II and Ill, and to a lesser extent complex IV, has been detected in the striatum of subjects with HD. Further, an N-terminal fragment of mutant huntingtin has been localized to the nucleus, and there is data to suggest that mutant huntingtin can alter gene expression. Considering these and other findings, it is of fundamental importance to determine how mutant huntingtin affects mitochondrial function, and further how these changes modulate the cellular toxicity of mutant huntingtin. Our overall working hypothesis is that mutant huntingtin compromises the function of mitochondria which results in altered cellular functions and an increased sensitivity of the neurons to specific stressors.
The specific aims of this proposal are to: (1) test the hypothesis that mutant huntingtin impairs mitochondrial function which sensitizes the cells to specific stressors, (2) test the hypothesis that expression of mutant huntingtin results in selective alterations in the expression of mitochondrial proteins involved in energy metabolism and (3) test the hypothesis that impaired mitochondrial function compromises proteasome activity and this results in alterations in huntingtin processing. Further, we hypothesize that this process is exacerbated in cells expressing mutant huntingtin. For these studies we will establish immortalized striatal neurons that inducibly express wild type and mutant huntingtin constructs. These studies will provide critically important data on the effects of mutant huntingtin on mitochondrial function and energy metabolism and provide insight into the mechanisms by which mutant huntingtin impairs mitochondrial function and contributes to the neurodegenerative processes in HD.
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