Regulation of mitochondrial morphology by alpha-synuclein

α-突触核蛋白对线粒体形态的调节

• 批准号: 8501699
• 负责人: KEN NAKAMURA
• 金额: $ 19.05万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/8501699
• 关键词: Address; Binding; Biological Assay; Cell physiology; Cells; Cellular Morphology; Development; Disease; Disease Progression; Economics; Electron Microscopy; Etiology; Human Genetics; Lead; Lewy Bodies; Mitochondria; Molecular; Morphology; Motor; Mutation; Nerve; Neurites; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathogenesis; Patients; Play; Process; Proteins; Regulation; Role; Substantia nigra structure; Symptoms; Testing; Time; Toxin; alpha synuclein; base; dopaminergic neuron; inhibitor/antagonist; insight; mitochondrial dysfunction; novel diagnostics; novel therapeutic intervention; research study; social; synuclein

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：帕金森氏病（PD）是一种常见且令人衰弱的神经退行性疾病，导致了实质性的社会和经济困难。当前的治疗纯粹是症状，并且随着时间的流逝失去了疗效，因为没有已知的方法可以减慢潜在的疾病进展。尽管我们不明白为什么细胞在PD中退化，但多种证据表明蛋白α-突触核蛋白和线粒体功能障碍在此过程中起着中心作用。我们发现，α-突触核蛋白通常与线粒体结合并产生其形态的巨大变化，这表明细胞功能和机制可能导致疾病。该建议将确定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中退化的细胞的后果。在特定目标1中，我们将使用互补方法来表征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效应，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。在特定目标2中，我们将确定α-核蛋白与线粒体结合并产生形态学变化的分子机制。首先，我们将确定α-突触核蛋白本地化的线粒体室。然后，我们将确定并比较结合和形态变化所需的α-核蛋白的特定域。我们还将评估已知的PD突变的影响，并确定产生该作用的突触核蛋白的多聚体状态。特定目标3通过检查α-核蛋白是否会改变神经终末线粒体的分布和迁移率，研究了α-突触核蛋白与线粒体在神经元中的影响。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的敏化作用。结果将有助于我们对PD发病机理的理解，并可能导致新的诊断和治疗方法的发展。相关性：拟议的实验将提供有关α-突触核蛋白对线粒体影响及其相互作用的影响的关键信息。结果将为帕金森氏病发生的原因提供新的见解，并可能构成开发新的诊断测定和修饰疗法疾病的基础。

项目成果

α-Synuclein and Mitochondria: Partners in Crime?

• DOI: 10.1007/s13311-013-0182-9
• 发表时间: 2013-07-01
• 期刊: NEUROTHERAPEUTICS
• 影响因子: 5.7
• 作者: Nakamura, Ken

Mitochondrial dynamics in neurodegeneration.

• DOI: 10.1016/j.tcb.2012.10.006
• 发表时间: 2013-02
• 期刊: Trends in cell biology
• 影响因子: 19
• 作者: Itoh K;Nakamura K;Iijima M;Sesaki H
• 通讯作者: Sesaki H

Energy failure: does it contribute to neurodegeneration?

• DOI: 10.1002/ana.24014
• 发表时间: 2013-10
• 期刊: ANNALS OF NEUROLOGY
• 影响因子: 11.2
• 作者: Pathak, Divya;Berthet, Amandine;Nakamura, Ken
• 通讯作者: Nakamura, Ken

Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis.

• DOI: 10.1016/j.neuron.2009.12.023
• 发表时间: 2010-01-14
• 期刊: NEURON
• 影响因子: 16.2
• 作者: Nemani, Venu M.;Lu, Wei;Berge, Victoria;Nakamura, Ken;Onoa, Bibiana;Lee, Michael K.;Chaudhry, Farrukh A.;Nicoll, Roger A.;Edwards, Robert H.
• 通讯作者: Edwards, Robert H.

Dynamin-related protein 1 is required for normal mitochondrial bioenergetic and synaptic function in CA1 hippocampal neurons.

• DOI: 10.1038/cddis.2015.94
• 发表时间: 2015-04-16
• 期刊: Cell death & disease
• 影响因子: 9
• 作者: Shields LY;Kim H;Zhu L;Haddad D;Berthet A;Pathak D;Lam M;Ponnusamy R;Diaz-Ramirez LG;Gill TM;Sesaki H;Mucke L;Nakamura K
• 通讯作者: Nakamura K