Autophagy and Protein Degradation in Parkinson's Disease Models

帕金森病模型中的自噬和蛋白质降解

• 批准号: 7663403
• 负责人: Asa Abeliovich
• 金额: $ 31.71万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7663403
• 关键词: Alzheimer' s Disease; Architecture; Autophagocytosis; Brain Pathology; Corpus striatum structure; Data; Defect; Disease; Disease model; Dopamine; Etiology; Genes; Inherited; Knockout Mice; Lead; Link; Lysosomes; Mediating; Modification; Morphology; Mus; Mutant Strains Mice; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; PTEN gene; Parkinson Disease; Parkinsonian Disorders; Pathology; Pathway interactions; Phenotype; Phosphorylation; Play; Proteins; Role; Signal Pathway; Signal Transduction; Starvation; Substantia nigra structure; Therapeutic; Time; Transgenic Animals; base; human FRAP1 protein; neuronal cell body; novel; protein degradation; public health relevance; stressor; tau Proteins

DESCRIPTION (provided by applicant): Several observations have linked neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease with altered intracellular protein degradation (1). Recently, autophagy mechanisms leading to lysosomal-mediated protein degradation have come into focus. Autophagy is an essential mechanism of protein degradation that is induced in the context of starvation and other stressors, and is a prominent feature in brain pathology in neurodegenerative diseases (3, 4), likely representing defects in the autophagy-lysosome pathway (5). Furthermore, mutations in lysosomal genes have been found to underlie rare familial inherited forms of Parkinsonism (6) and associated with common sporadic PD(3). Key questions exist: i. Do autophagy defects recapitulate aspects of neurodegenerative disorders? ii. By what mechanism does altered autophagy in mDNs lead to pathological and morphological changes? We hypothesize, based on preliminary data, that: i. Autophagy plays a central role in regulating the survival and morphology of mDNs, and deficiency of autophagy recapitulates key aspects of neurodegenerative pathology, including accumulation of disease-associated proteins. ii. A novel mechanism by which autophagy defects lead to pathology is through direct (but non- canonical) downstream modification of the PI3K/PTEN/AKT/GSK3beta/Tau signaling pathway; this relates specifically to altered accumulation of signaling pathway components. iii. The altered PI3K/PTEN/AKT/GSK3beta/Tau pathway signaling plays a causal role in the phenotypes associated with autophagy deficiency. PUBLIC HEALTH RELEVANCE: Several observations have linked Parkinson<s disease (PD) with altered intracellular protein degradation. Here we investigate the role of autophagy, a mechanism of protein degradation, in neuron survival and function in the context of PD models, and we relate autophagy to a key cellular signaling mechanism. We propose to identify novel potential therapeutics for PD that function in this pathway.

描述（由申请人提供）：多项观察结果表明帕金森病 (PD) 和阿尔茨海默病等神经退行性疾病与细胞内蛋白质降解的改变有关 (1)。最近，导致溶酶体介导的蛋白质降解的自噬机制已成为人们关注的焦点。自噬是蛋白质降解的一种重要机制，在饥饿和其他应激源的情况下诱发，并且是神经退行性疾病脑病理学的一个突出特征 (3, 4)，可能代表自噬-溶酶体途径的缺陷 (5)。此外，溶酶体基因突变已被发现是罕见的家族遗传性帕金森病的基础 (6) 并与常见的散发性帕金森病相关 (3)。存在的关键问题是： i．自噬缺陷是否概括了神经退行性疾病的各个方面？二. mDN 中自噬的改变通过什么机制导致病理和形态学变化？根据初步数据，我们假设： i．自噬在调节 mDN 的存活和形态方面发挥着核心作用，自噬的缺陷概括了神经退行性病理学的关键方面，包括疾病相关蛋白的积累。二.自噬缺陷导致病理的一种新机制是通过直接（但非规范）下游修饰 PI3K/PTEN/AKT/GSK3beta/Tau 信号通路；这特别与信号通路成分积累的改变有关。三. PI3K/PTEN/AKT/GSK3beta/Tau 通路信号传导的改变在与自噬缺陷相关的表型中起着因果作用。公共健康相关性：一些观察结果表明帕金森病 (PD) 与细胞内蛋白质降解的改变有关。在这里，我们研究了自噬（一种蛋白质降解机制）在 PD 模型中神经元存活和功能中的作用，并将自噬与关键的细胞信号传导机制联系起来。我们建议寻找在该途径中发挥作用的帕金森病的新型潜在疗法。