Modulating selective autophagy to modify Huntington's disease

调节选择性自噬以改变亨廷顿病

• 批准号: 9765866
• 负责人: Ai Yamamoto
• 金额: $ 41.54万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765866
• 关键词: Adaptor Signaling Protein; Adult; Age; Age of Onset; Appearance; Autophagocytosis; Behavioral; Biological Models; Brain; Cell model; Cells; Cellular biology; Code; Cytoplasmic Protein; Disease; Funding; Genetic; Genetic study; Huntington Disease; Huntington gene; Kinetics; Life; Link; Lipids; Lysosomes; Mediating; Modeling; Molecular; Mus; Neurodegenerative Disorders; Neurons; Nuclear Export; Nuclear Localization Signal; Nuclear Proteins; Onset of illness; Orthologous Gene; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Phenotype; Plant Roots; Play; Proteins; Role; Stress; System; Testing; Therapeutic; Variant; Venezuelan; WD Repeat; Work; base; cohort; genetic variant; in vivo; mouse model; mutant; protein aggregate; protein aggregation; protein expression; rare variant; reduce symptoms; scaffold; therapy outcome

PROJECT SUMMARY Although a common theme across adult onset neurodegenerative diseases, the pathogenic role of aggregated proteins is a continuous topic of debate. For the incurable familial neurodegenerative disorder Huntington's disease (HD), resolving the accumulation of mutant huntingtin (Htt) (neuronal or cytoplasmic) is highly correlated with favorable therapeutic outcomes. Whether targeting aggregate clearance per se is beneficial, however, has remained unclear. We have previously identified a pathway by which aggregated proteins are selectively eliminated by the lysosome-mediated pathway macroautophagy. We found that the protein Alfy is central for the selective turnover of aggregates in cell based systems. During the previous funding period, we used a mouse genetics and cell biology to determine that Alfy is indeed essential turnover of aggregated proteins in adult brain, and diminishing Alfy levels in vivo modifies disease onset. In this renewal application, we will use genetic and molecular based approaches to determine if augmenting Alfy levels promotes the elimination of aggregated nuclear and cytoplasmic proteins, the mechanism by which a genetic variant of Alfy might delay the age of onset of MD, and the molecular mechanism by which Alfy permits aggregate clearance. .

项目摘要 尽管神经退行性疾病的共同主题，但聚集的致病作用 蛋白质是辩论的连续主题。对于无法治愈的家族性神经退行性疾病亨廷顿 疾病（HD），解决突变体亨廷汀（HTT）（神经元或细胞质）的积累高度相关 具有良好的治疗结果。然而，针对骨料清除本身是否有益 仍然不清楚。我们以前已经确定了汇总蛋白有选择性的途径 被溶酶体介导的途径大量自噬所消除。我们发现蛋白质Alfy是中心的 基于细胞系统中聚集体的选择性营业额。在上一个资金期间，我们使用了鼠标 遗传学和细胞生物学以确定ALFY确实是成人大脑中综合蛋白的必不可少的， 体内的ALFY水平降低会改变疾病的发作。在此续签应用中，我们将使用遗传和 基于分子的方法来确定增加ALFY水平是否促进了消除聚合 核和细胞质蛋白，ALFY遗传变异的机制可能会延迟发作的年龄 MD和ALFY允许骨料清除的分子机制。 。