ATP13A2 and Susceptibility to Neurodegeneration

项目摘要/摘要 与年龄相关的神经退行性疾病对数百万人的健康和经济构成越来越大的威胁 每年。遗传易感性、环境暴露和年龄都会增加罹患癌症的风险 神经退行性疾病，如共核病和锰中毒。ATPase ATP13A2是 与包括帕金森氏症在内的多种年龄相关的神经退行性疾病有关，最多的 常见的突触核病、神经元性干酪样脂褐质沉着症和锰中毒可能是 将关键的神经退行性疾病风险因素联系起来的蛋白质。基因-环境相互作用的鉴定 与神经变性相关的疾病是早期发现、预防和治疗的重要步骤。这个 这项建议的目的是确定ATP13A2如何参与线粒体的维护以及它是如何 与环境和遗传风险因素相互作用，导致神经退化。据推测， ATP13A2功能丧失使神经元更容易受到锰和α-突触核蛋白的毒性 通过参与线粒体维持的机制，包括修复和清除机制。 此外，这种干扰可能与衰老和蛋白质积累相互作用，从而产生增强的 神经退行性变和行为障碍。我们最近的数据显示，ATP13A2的功能丧失在 小鼠对锰的反应增强，大脑病理加重。指导原则 初步数据这一假设将通过追求三个具体目标来检验：1)确定 ATP13A2功能缺失对体内线粒体维持的影响，2)评估神经毒性后果 在存在ATP13A2缺失的情况下，锰暴露对脑和外周组织线粒体功能的影响 确定ATP13A2功能丧失和α-突触核蛋白负荷增加对线粒体的影响 体内的维护和生物能量学。这些研究的结果预计将产生积极的影响 根据我们对基因-环境相互作用如何导致细胞功能障碍的理解， 神经退行性变和行为障碍。

Project Summary/Abstract Age-related neurodegenerative diseases are an increasing health and economic threat for millions of people each year. Genetic susceptibility, environmental exposures, and age can all increase the risk of developing neurodegenerative conditions such as synucleinopathies and manganism. The ATPase ATP13A2 is associated with multiple age-related neurodegenerative conditions including Parkinson’s disease, the most common synucleinopathy, Neuronal Ceroid Lipofuscinosis, and manganism and may be an important protein linking key neurodegenerative disease risk factors. Identification of gene-environment interactions associated with neurodegeneration is an important step to early detection, prevention, and treatment. The objective of this proposal is to determine how ATP13A2 is involved in mitochondrial maintenance and how it interacts with environmental and genetic risk factors to cause neurodegeneration. It is hypothesized that loss of ATP13A2 function makes neurons more vulnerable to manganese and alpha-synuclein toxicity through mechanisms involved in mitochondrial maintenance including repair and clearance mechanisms. Further, this disruption may interact with aging and protein accumulation to produce enhanced neurodegeneration and behavioural dysfunction. Our recent data shows that loss of function of ATP13A2 in mice leads to an enhanced response to manganese and increased pathology in the brain. Guided by preliminary data this hypothesis will be tested by pursuing three specific aims: 1) Determine the impact of loss of ATP13A2 function on mitochondrial maintenance in vivo, 2) Assess the neurotoxic consequences of Mn exposure in the presence of ATP13A2 loss on mitochondrial function in brain and periphery, and 3) Identify the impact of loss of ATP13A2 function and increased alpha-synuclein burden on mitochondrial maintenance and bioenergetics in vivo. Results from these studies are expected to have a positive impact on our understanding of how gene-environment interactions can contribute to cellular dysfunction, neurodegeneration, and behavioral impairments.