Regulation of mitochondrial morphology by alpha-synuclein

α-突触核蛋白对线粒体形态的调节

基本信息

批准号：
7659837
负责人：
KEN NAKAMURA
金额：
$ 16.51万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): PROJECT SUMMARY: Parkinson's disease (PD) is a common and debilitating neurodegenerative disorder, resulting in substantial social and economic hardships. Current therapy is purely symptomatic and loses efficacy over time, as there is no known way to slow the underlying disease progression. Although we do not understand why cells degenerate in PD, multiple lines of evidence indicate that the protein alpha-synuclein and mitochondrial dysfunction play central roles in this process. We have found that alpha-synuclein normally binds to mitochondria and produces a dramatic change in their morphology, suggesting a cellular function and mechanism that might contribute to disease. This proposal will determine the mechanism by which alpha-synuclein binds and induces morphologic changes in mitochondria, as well as the consequences of these changes to cells that degenerate in PD. In Specific Aim 1, we will use complementary approaches to characterize the effects of alpha-synuclein on mitochondrial morphology. These will include electron microscopy to visualize the ultrastructural effects of alpha-synuclein on mitochondrial morphology, and cellular approaches in which we test whether known inhibitors can block alpha-synuclein from producing morphologic change. In Specific Aim 2, we will determine the molecular mechanisms by which alpha-synuclein binds to mitochondria and produces morphologic changes. First, we will determine the mitochondrial compartment to which alpha-synuclein localizes. We will then identify and compare the specific domains of alpha-synuclein that are required for binding and morphologic change. We will also assess the effects of known PD mutations, and determine the multimeric state of synuclein that produces the effect. Specific Aim 3 investigates the consequences of alpha-synuclein's interactions with mitochondria in neurons, by examining whether alpha-synuclein changes the distribution and mobility of mitochondria at the nerve terminal. We will also determine whether interactions with mitochondria contribute to alpha-synuclein's known effects of sensitizing to mitochondrial toxins. The results will contribute to our understanding of PD pathogenesis, and may lead to the development of new diagnostic and therapeutic approaches. RELEVANCE: The proposed experiments will provide critical information concerning alpha-synuclein's effects on mitochondria and the consequences of this interaction. The results will provide new insights into why Parkinson's disease occurs, and may form the basis for the development of new diagnostic assays and disease modifying therapies.

描述（由申请人提供）：项目摘要：帕金森病 (PD) 是一种常见且使人衰弱的神经退行性疾病，会导致严重的社会和经济困难。目前的治疗纯粹是针对症状的，并且随着时间的推移会失去疗效，因为没有已知的方法可以减缓潜在的疾病进展。尽管我们不明白为什么细胞会在帕金森病中退化，但多种证据表明蛋白质α-突触核蛋白和线粒体功能障碍在此过程中发挥着核心作用。我们发现，α-突触核蛋白通常与线粒体结合，并使其形态发生巨大变化，这表明可能导致疾病的细胞功能和机制。该提案将确定 α-突触核蛋白结合并诱导线粒体形态变化的机制，以及这些变化对 PD 中退化细胞的影响。在具体目标 1 中，我们将使用补充方法来表征 α-突触核蛋白对线粒体形态的影响。这些将包括电子显微镜以可视化α-突触核蛋白对线粒体形态的超微结构影响，以及我们测试已知抑制剂是否可以阻止α-突触核蛋白产生形态变化的细胞方法。在具体目标 2 中，我们将确定 α-突触核蛋白与线粒体结合并产生形态变化的分子机制。首先，我们将确定 α-突触核蛋白定位的线粒体区室。然后，我们将识别并比较结合和形态变化所需的 α-突触核蛋白的特定结构域。我们还将评估已知 PD 突变的影响，并确定产生该影响的突触核蛋白的多聚体状态。具体目标 3 通过检查 α-突触核蛋白是否改变神经末梢线粒体的分布和活动性，研究 α-突触核蛋白与神经元中线粒体相互作用的后果。我们还将确定与线粒体的相互作用是否有助于 α-突触核蛋白对线粒体毒素敏感的已知作用。这些结果将有助于我们对帕金森病发病机制的理解，并可能导致新的诊断和治疗方法的开发。相关性：拟议的实验将提供有关 α-突触核蛋白对线粒体的影响以及这种相互作用的后果的关键信息。这些结果将为帕金森病发生的原因提供新的见解，并可能成为开发新的诊断测定和疾病修饰疗法的基础。