Genetic analysis of mitochondria-dependent cellular toxicity of alpha-synuclein

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Proteinaceous inclusions are common pathological features of Alzheimer’s disease and degenerative dementias. Lewy body, containing insoluble misfolded α-synuclein, is the predominant protein pathology of Lewy body dementia. In autopsied brain tissues from patients, Lewy body and Lewy-related pathology frequently co-occur with neurofibrillary Tau tangles and A plaques, two pathological hallmarks of Alzheimer’s disease. The excessive co-occurrence of protein pathology in patients with degenerative dementia is indicative of common neurological mechanisms underlying aberrant protein misfolding, accumulation and progressive deposition. Mitochondrial damage and dysfunction are thought to be one of such common mechanisms. This proposal employs a novel cellular model that enables the expression of aggregation prone proteins while forcing cells to undergo mitochondria-dependent respiration. Consistent with a role of mitochondria in driving protein pathology, α-synuclein and a few other neurodegenerative disease-associated proteins become exceedingly more toxic as cells are forced to respire. Toxicity coincides with elevated formation of cytoplasmic protein inclusions and pronounced mitochondrial damages. Systematic genetic screens identified human genes that protect cells from the toxicity of several aggregation prone proteins, including α-synuclein and TDP-43, which is associated with Frontotemporal dementia. Genetic screens also identified human genes that enhance the toxicity with a significant fraction of those enhancer genes having known mitochondrial related functions. These findings lead to the premise of the proposal that mitochondria act as a driving force to regulate protein misfolding and toxicity. Two specific aims are outlined to characterize the regulatory effects of the identified human-gene suppressors and enhancers with a particular focus on mitochondrial function and dysfunction. Completion of the proposed work will reveal new roles of mitochondria in modulating the toxicity of aggregation prone proteins and identify cellular targets that drive common protein pathology in Alzheimer’s disease and degenerative dementia.