The Role of Lysosomal Dysfunction in Parkinson Disease-Related Neurodegeneration

溶酶体功能障碍在帕金森病相关神经变性中的作用

• 批准号: 8595655
• 负责人: Lauren Rebecca Kett
• 金额: $ 2.92万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8595655
• 关键词: ATP phosphohydrolase; Age; Age-Months; Animal Model; Autophagocytosis; Autophagosome; Binding; Biochemical; Brain region; Cellular Stress; Defect; Degradation Pathway; Dementia; Detergents; Disease; Dyskinetic syndrome; Electron Microscopy; Ensure; Enzymes; Fractionation; Functional disorder; Gaucher Disease; Genes; Gliosis; Goals; Health; Homeostasis; Impairment; In Vitro; Inflammation; Inherited; Knockout Mice; Knowledge; Lead; Learning; Link; Lysosomes; Membrane; Methods; Motor; Movement Disorders; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neuronal Injury; Neurons; Organelles; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathway interactions; Peptide Hydrolases; Phenotype; Process; Proteins; Psychotic Disorders; Publishing; Relative (related person); Risk; Role; Scientist; Staining method; Stains; System; Testing; Time; Toxic effect; Training; Ubiquitin; Waste Products; Work; age related; aged; alpha synuclein; cerebral atrophy diffuse; early onset; glucosylceramidase; human disease; in vivo; insight; loss of function; lysosomal proteins; motor deficit; mouse model; mutant; neuropathology; neurotoxicity; novel; protein aggregate; protein aggregation; protein degradation; protein misfolding; public health relevance; relating to nervous system; research study; skills; synuclein; trafficking

DESCRIPTION (provided by applicant): To maintain health, neurons must clear misfolded or mutant proteins in a timely manner, utilizing several pathways for protein degradation. The autophagic-lysosomal system allows cytosolic proteins to be trafficked into specific organelles where they are degraded by lysosomal proteases. Deficits in autophagy have been implicated in many neurodegenerative disorders including Parkinson disease (PD). Alpha-synuclein, a key protein that aggregates in PD, is degraded by autophagy and mutations in several lysosomal enzymes have been linked to familial forms of Parkinsonism. Recent work has focused on how loss of GBA, the gene encoding lysosomal glucocerebrosidase and deficient in Gaucher's disease, leads to an increased risk of PD. Loss of ATP13A2, a lysosomal ATPase, similarly results in a familial form of Parkinsonism, likely through alterations to autophagy. The objective of this proposal is to determine how loss of lysosomal ATP13A2 results in autophagic deficits and PD pathogenesis. I have developed a novel mouse model of PD in which loss of endogenous Atp13a2 results in age-related motor abnormalities and neuropathology. To better understand the mechanism underlying these deficits, I will test the specific hypothesis that loss of Atp13a2 results in impairment of the autophagic-lysosomal system, which in turn causes protein aggregation, neuronal dysfunction, and motor deficits. I will develop this hypothesis with two aims: 1) Determine ultrastructurally how loss of Atp13a2 alters intermediates in the autophagic-lysosomal system and 2) Determine the sequence and timing of lysosome accumulation and protein aggregation in Atp13a2 null mice. Under Aim 1, I will use electron microscopy to determine the relative abundance of specific autophagic intermediates in wildtype and Atp13a2 null mice. Under Aim 2, I will assess Atp13a2 null and wildtype mice at different ages to determine the onset of protein aggregation, lysosomal accumulation, and alpha-synuclein insolubility. The experiments outlined in this proposal are expected to contribute fundamental knowledge to the function of ATP13A2 within the lysosome, as well as how loss of ATP13A2 results in KRD. These results will contribute more broadly to understanding the role of the lysosome in PD pathogenesis.

描述(申请人提供)：为了保持健康，神经元必须利用几种蛋白质降解途径，及时清除错误折叠或突变的蛋白质。自噬-溶酶体系统允许胞浆蛋白被运输到特定的细胞器，在那里它们被溶酶体蛋白酶降解。自噬缺陷与包括帕金森病(PD)在内的许多神经退行性疾病有关。α-突触核蛋白是聚集在帕金森病中的一种关键蛋白，它通过自噬降解，几种溶酶体酶的突变与家族性帕金森综合症有关。最近的工作集中在GBA基因的缺失上，GBA是编码溶酶体葡萄糖脑苷酶的基因，在高谢病中缺乏，如何导致帕金森病风险增加。ATP13A2，一种溶酶体ATPase的缺失，类似地导致家族性帕金森氏症，可能是通过自噬的改变。本研究的目的是确定溶酶体ATP13A2缺失如何导致自噬缺陷和帕金森病的发病机制。我开发了一种新的帕金森病小鼠模型，在该模型中，内源性Atp13a2的缺失会导致与年龄相关的运动异常和神经病理。为了更好地理解这些缺陷背后的机制，我将测试特定的假设，即Atp13a2的缺失会导致自噬-溶酶体系统的损伤，进而导致蛋白质聚集、神经元功能障碍和运动障碍。我提出这个假说有两个目的：1)从超微结构上确定Atp13a2的缺失如何改变自噬-溶酶体系统中的中间产物；2)确定Atp13a2缺失小鼠中溶酶体积累和蛋白质聚集的顺序和时间。在目标1中，我将使用电子显微镜来确定野生型和Atp13a2缺失小鼠体内特定自噬中间体的相对丰度。在目标2下，我将评估不同年龄的Atp13a2缺失和野生型小鼠，以确定蛋白质聚集、溶酶体积累和α-突触核蛋白不溶的开始。这项提案中概述的实验有望为ATP13A2在溶酶体中的功能以及ATP13A2丢失如何导致KRD提供基础知识。这些结果将有助于更广泛地了解溶酶体在帕金森病发病机制中的作用。