Determining Selective Autophagy Kinase in Modulating Neurotoxicity in Huntington's Disease Model

我们的目标是阐明亨廷顿病（HD）中神经保护性自噬的分子机制， 确定选择性自噬在治疗疾病中的治疗潜力。HD是由一种异常的 HTT基因中CAG重复序列（polyQ）的扩增，导致突变体中的毒性功能获得性 亨廷顿蛋白（mHTT）。尽管有20多年的研究，但仍然没有改善疾病的治疗方法。 因此，阐明疾病机制和mHTT清除途径是成功治疗的关键。 治疗发展自噬是一种分解代谢的细胞途径， 细胞器通过溶酶体作为质量控制系统。PolyQ扩增的蛋白质聚集体，包括 HTT的片段可以通过选择性自噬降解，因此选择性自噬被认为是药物 HD的目标然而，自噬是一个受到严格调控的复杂过程， 自噬选择性降解mHTT仍然知之甚少。我们之前的研究表明，ULK1调节 蛋白毒性应激下p62介导的选择性自噬。然而，在mHTT的背景下，我们报告说， ULK1激酶活性失调，与VPS34活性降低和异常p62选择性 HD模型zQ175的脑中的自噬。我们目前的研究表明，ULK1缺乏会加速 mHTT介导的毒性。因此，这些数据为ULK1-p62介导的选择性细胞凋亡的作用提供了强有力的证据。 自噬调节mHTT毒性。我们假设ULK1和p62是HD的有希望的调节剂， 疾病进展。我们建议（1）确定ULK1-p62信号转导在肿瘤细胞中的作用和机制。 通过选择性自噬降解mHTT;（2）探讨mHTT的致病机制， 破坏ULK1激酶活性并引起ULK1缺陷介导的选择性自噬损伤， 神经毒性;（3）确定ULK1激酶活性作为抑制mHtt介导的神经毒性的治疗靶点 通过遗传学和药理学方法使用动物模型。我们的研究有望揭示 ULK1抗HD保护功能的分子机制，并验证ULK1激酶作为药物的活性 靶向清除mHTT并提供神经保护。

Our goal is to elucidate molecular mechanism for neuroprotective autophagy in Huntington's disease (HD) and determine therapeutic potential for selective autophagy in treating the disease. HD is caused by an aberrant expansion of CAG repeat (polyQ) in the HTT gene, which leads to a toxic gain-of-function in the mutant huntingtin (mHTT) protein. Despite over 20 years' research, disease-modifying therapeutics is unavailable. Thus, elucidation of the disease mechanism and mHTT clearance pathways is pivotal for the success of therapeutic development. Autophagy is a catabolic cellular pathway that clears protein aggregates and injured organelles through lysosomes as a quality control system. PolyQ-expanded protein aggregates including fragments of HTT can be degraded by selective autophagy, and thus selective autophagy is considered a drug target for HD. However, autophagy is a complex process subjected to tight regulation, and how exactly autophagy selectively degrade mHTT remains poorly understood. We previously showed that ULK1 regulates p62-mediated selective autophagy under proteotoxic stress. In the context of mHTT, however, we reported dysregulation of ULK1 kinase activity that connects to reduced VPS34 activity and aberrant p62-selective autophagy in the brains of HD model zQ175. Our current study suggests that ULK1 deficiency accelerates mHTT-mediated toxicity. The data thus provides strong evidence for the role of ULK1-p62 mediated selective autophagy in regulating mHTT toxicity. We hypothesize that ULK1 and p62 are promising modifiers of HD disease progression. We propose (1) to determine the role and mechanism for ULK1-p62 signaling in the degradation of mHTT through selective autophagy; (2) to investigate pathogenic mechanism that mHTT disrupts ULK1 kinase activity and causes ULK1 deficiency-mediated selective autophagy impairment and neurotoxicity; (3) determine ULK1 kinase activity as a therapeutic target to inhibit mHtt-mediated neurotoxicity using animal models through genetic and pharmacological approaches. Our study is expected to reveal molecular mechanism for ULK1 protective function against HD and validate ULK1 kinase activity as a drug target for the clearance of mHTT and offering neuroprotection.