Autophagy and Protein Degradation in Parkinson's Disease Models

描述(由申请人提供)：一些观察将帕金森氏病(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改变联系在一起(1)。最近，导致溶酶体介导的蛋白质降解的自噬机制已经成为人们关注的焦点。自噬是在饥饿和其他应激源的背景下诱导蛋白质降解的一种基本机制，也是神经退行性疾病的大脑病理的一个显著特征(3，4)，可能代表自噬-溶酶体途径的缺陷(5)。此外，溶酶体基因突变被发现是罕见的家族性遗传性帕金森病的基础(6)，并与常见的散发性帕金森病有关(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某些方面？二、MDN中改变的自噬通过什么机制导致病理和形态变化？基于初步数据，我们假设：i.自噬在调节mDns的存活和形态方面起着核心作用，自噬缺陷重现了神经退行性病理的关键方面，包括疾病相关蛋白的积累。二、自噬缺陷导致病理改变的一个新机制是通过直接(但非典型的)下游修饰PI3K/PTEN/AKT/GSK3β/Tau信号通路；这特别与信号通路成分的改变积累有关。三、PI3K/PTEN/AKT/GSK3β/Tau信号通路的改变在自噬缺陷的表型中起着因果作用。公共卫生相关性：几项观察将帕金森和S病(PD)与细胞内蛋白质降解改变联系在一起。在这里，我们研究了自噬，一种蛋白质降解的机制，在帕金森病模型的背景下，在神经元生存和功能中的作用，我们将自噬与一个关键的细胞信号机制联系起来。我们建议寻找在这一途径中发挥作用的帕金森病的新的潜在治疗方法。

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.