Determining selective autophagy kinase in modulating neurotoxicity in Huntington's disease model

确定选择性自噬激酶在亨廷顿病模型中调节神经毒性的作用

基本信息

批准号：
10438575
负责人：
Zhenyu Yue
金额：
$ 46.79万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10438575
关键词：
Age Agonist Amino Acid Sequence Animal Model Antisense Oligonucleotides Autophagocytosis Axon Biological Markers Body Weight Brain CAG repeat CRISPR/Cas technology Cell model Cells Clinical Trials Complex DNA Data Disease Disease Progression Disease model Drug Targeting Functional disorder GTF2H1 gene Genes Genetic Genetic Transcription Goals Huntington Disease Huntington gene Huntington protein Impairment Knock-in Knockout Mice Lysosomes Mediating Mendelian disorder Methods Mitochondria Molecular Mus Nuclear Inclusion Nuclear Pore Complex Oral Organelles Pathogenicity Pathway interactions Pharmacology Phenotype Phosphotransferases Physiological Post-Translational Protein Processing Process Proteins Proteomics Quality Control RNA RNA Interference RNA Splicing Refractory Regulation Reporting Research Resistance Role Scaffolding Protein Signal Transduction Stress Symptoms Synapses System Techniques Testing Therapeutic Toxic effect Toxicity Tests excitotoxicity gain of function injured mouse model mutant neuroprotection neurotoxicity novel overexpression oxidative damage polyglutamine postnatal prevent protein aggregation proteostasis proteotoxicity response small molecule success therapeutic development therapeutic target trafficking

项目摘要

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.

我们的目标是阐明亨廷顿病（HD）和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 是由异常引起的 HTT 基因中 CAG 重复序列 (polyQ) 的扩展，导致突变体出现毒性功能获得亨廷顿蛋白（mHTT）。尽管经过 20 多年的研究，仍无法找到缓解疾病的疗法。因此，阐明疾病机制和 mHTT 清除途径对于治疗成功至关重要。治疗的发展。自噬是一种分解代谢细胞途径，可清除蛋白质聚集物和损伤通过溶酶体作为质量控制系统的细胞器。 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来降解，因此选择性自噬被认为是一种药物高清目标。然而，自噬是一个受到严格调控的复杂过程，并且到底如何进行自噬选择性降解 mHTT 仍知之甚少。我们之前表明 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 ULK1 激酶活性失调与 VPS34 活性降低和 p62 选择性异常有关 HD 模型 zQ175 大脑中的自噬。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 是有希望的 HD 修饰剂疾病进展。我们建议 (1) 确定 ULK1-p62 信号传导在通过选择性自噬降解 mHTT； (2)探讨mHTT的致病机制破坏 ULK1 激酶活性并导致 ULK1 缺乏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和药理学方法使用动物模型。我们的研究预计将揭示 ULK1 对 HD 保护功能的分子机制并验证 ULK1 激酶作为药物的活性清除 mHTT 并提供神经保护的目标。