Autophagy and Protein Degradation in Parkinson's Disease Models

描述（由申请人提供）：一些观察结果将神经退行性疾病（如帕金森病（PD）和阿尔茨海默病）与细胞内蛋白质降解改变联系起来（1）。最近，导致溶酶体介导的蛋白质降解的自噬机制已成为焦点。自噬是在饥饿和其他应激源的背景下诱导的蛋白质降解的基本机制，并且是神经退行性疾病的脑病理学中的突出特征（3，4），可能代表自噬-溶酶体途径中的缺陷（5）。此外，已发现溶酶体基因突变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PD相关（3）。存在的主要问题：一。自噬缺陷是否概括了神经退行性疾病的各个方面？二. mDNs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mDNs的存活和形态中起着核心作用，自噬的缺乏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新机制是通过PI 3 K/PTEN/AKT/GSK 3 β/Tau信号传导途径的直接（但非经典）下游修饰;这具体涉及信号传导途径组分的改变的积累。三.改变的PI 3 K/PTEN/AKT/GSK 3 β/Tau通路信号传导在与自噬缺陷相关的表型中起因果作用。公共卫生相关性：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，我们研究了自噬的作用，蛋白质降解的机制，在神经元的生存和功能的背景下，PD模型，我们与自噬的一个关键的细胞信号传导机制。我们建议确定新的潜在治疗PD的功能在这一途径。

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.