(provided by canddiate): The goal of this proposal is to delineate the molecular mechanisms of mutant huntingtin (Htt) protein clearance. The expression and accumulation of mutant Htt protein plays a key role in the pathogenesis of Huntington's disease. Enhancing the selective clearance of miJtant Htt protein will likely contribute to halting or reversing disease progression. Current approaches to enhance clearance of mutant Htt protein result in global or nonspecific activation of autophagy and other cellular pathways that could have deleterious effects in neurons. Our previous work has shown that acetylation of Htt protein occurs selectively on the mutant, but not wild type protein. Acetylation enhances clearance of mutant Htt through an autophagic-lysosomal degradation pathway, however the specific proteins involved in this process are not known. Here, I will attempt to determine the molecular machinery involved in selective targeting of the acetyl-mutant Htt substrate to the autophagosome. This will contibute toward our understanding of how mutant Htt is degraded in neurons, leading to new therapeutic targets for Huntinton's disease. These experiments will also uncover basic mechanisms of the autophagic process in healthy and diseased neurons, and how these cells adapt or selectively degrade toxic substrates in the cell. These pathways are also likely to be relevant to other neurodegenerative diseases that contain pathogenic misfolded protiens, such as Alzheimer's and Parkinson's disease. Huntington's disease affects over 30,000 individuals in the USA and there are more than 70,000 individuals who are likely premanifest gene carriers. Our work will contribute to understanding how neurons regulate mutant huntingtin protein levels, a process that is critically involved in the pathogenesis of Huntington's disease. Focusing on degradation mechanisms that are specific for the mutant form of the protein, these studies should provide novel therapeutic strategies that will lead to treatments for patients at both early and late stages of Huntington's disease progression.
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