Mechanisms of Mutant Huntington Clearance by Autophagy

描述（由候选人提供）：本提案的目标是描述突变型亨廷顿蛋白（Htt）蛋白清除的分子机制。突变Htt蛋白的表达和积累在亨廷顿病的发病机制中起着关键作用。增强对重要Htt蛋白的选择性清除可能有助于阻止或逆转疾病进展。目前增强突变Htt蛋白清除的方法导致自噬和其他可能对神经元产生有害影响的细胞途径的全局或非特异性激活。我们之前的工作表明，Htt蛋白的乙酰化选择性地发生在突变体上，而不是野生型蛋白上。乙酰化通过自噬-溶酶体降解途径增强突变体Htt的清除，但参与该过程的特定蛋白质尚不清楚。在这里，我将尝试确定参与选择性靶向乙酰基突变Htt底物到自噬体的分子机制。这将有助于我们理解突变的Htt如何在神经元中降解，从而为亨廷顿氏病找到新的治疗靶点。这些实验还将揭示健康和患病神经元自噬过程的基本机制，以及这些细胞如何适应或选择性地降解细胞中的有毒底物。这些途径也可能与其他含有致病性错误折叠蛋白的神经退行性疾病有关，如阿尔茨海默病和帕金森病。在美国，亨廷顿舞蹈病影响了3万多人，有7万多人可能是先兆基因携带者。我们的工作将有助于理解神经元如何调节突变的亨廷顿蛋白水平，这一过程在亨廷顿病的发病机制中至关重要。这些研究的重点是蛋白质突变形式特异性的降解机制，这些研究将提供新的治疗策略，从而为亨廷顿病进展的早期和晚期患者提供治疗。

DESCRIPTION (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.