Mitochondrial Fission in Huntington's Disease

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DESCRIPTION (provided by applicant): Huntington's disease (HD) is a hereditary neurodegenerative disorder and is caused by an abnormal polyglutamine (polyQ) expansion in the huntingtin (htt) protein, leading to progressive dementia, motor defects and psychiatric abnormalities. Presently, HD remains without cure. In HD striatal and cortical neurons die selectively by an unknown mechanism. Scientific breakthroughs are desperately needed to unravel how mutant htt causes neuronal demise. New evidence emerged indicating that mitochondrial dysfunction plays a central role in the pathogenesis underlying HD. But, exactly how mitochondria become injured in HD remains unclear. Mitochondria are dynamic organelles able to migrate, divide (undergo fission) and to fuse. Mitochondrial fission and fusion is choreographed by dynamin-related GTPases with competing activities. At normal conditions mitochondria form cable-like filaments in neurons, allowing efficient energy transmission, mixing of metabolites, Ca2+ buffering, and silencing of mtDNA mutations. Here, we will test the novel hypothesis whether persistent mitochondrial fission represents a mechanistic basis for the mitochondrial dysfunction implicated in HD pathogenesis. We will address the following questions: (1) Does mutant htt trigger continuous mitochondrial fission, which in turn results in ultrastructural damage of mitochondria, energy deficits, impaired mitochondrial respiration, ROS production, abnormal Ca2+ homeostasis, and mtDNA loss? (2) Does mutant htt recruit and activate the mitochondrial fission machinery? (3) Does mitochondrial fission play a causal role in mutant htt-induced neurodegeneration and cell death? To answer these questions we will isolate primary striatal or cortical neurons. Additionally, we will employ mutant htt transgenic mice and postmortem HD brain tissue. We will analyze them using interdisciplinary and advanced techniques including 3D timelapse imaging, EM tomography, molecular genetics, pharmacology, biochemistry, and bioenergetics. We will also develop new algorithms to quantify mitochondrial fission and mthtt aggregate formation by 3D time-lapse imaging. This study will improve our basic understanding of how mutant htt triggers neuronal demise. Results obtained here may offer a new mechanistic basis for the metabolic and mitochondrial defects underlying HD and perhaps other polyQ disease. Most importantly, this study may bring new hopes for effective treatments to conquer progressive neuron loss in HD, so patients can lead improved lives.