MITOCHONDRIAL FISSION AND NEURODEGENERATION

线粒体裂变和神经变性

基本信息

批准号：
8361903
负责人：
Ella R Bossy-Wetzel
金额：
$ 3.95万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8361903
关键词：
Agreement Apoptotic Bacterial Toxins Binding Buffers Calcium Cell Death Cell physiology Cells Chronic Complex Defect Dynamin Equilibrium Event Exhibits Exocytosis Family Filament Free Radicals Funding Future Grant Guanosine Triphosphate Phosphohydrolases Human Image Analysis Link Mediating Membrane Membrane Fusion Mitochondria Mitochondrial DNA NADH dehydrogenase (ubiquinone)National Center for Research Resources Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Outer Mitochondrial Membrane Oxidative Stress Parkinson Disease Patients Prevention Principal Investigator Production Proteins Publications Research Research Infrastructure Resources SNAP receptor Site Source Structure Synapses Testing Transgenic Mice United States National Institutes of Health alpha synuclein brain tissue cost mitochondrial DNA mutation mitochondrial dysfunction mitochondrial membrane mutant neuron loss neurotoxicity overexpression prevent protein aggregation respiratory

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We are using NCMIR to study Parkinson's disease (PD) and related neurodegenerative disorders. We hypothesize that alpha-synuclein (a-syn) causes neurodegeneration by inducing chronic mitochondrial fission through abnormal interaction with mitochondrial fission and fusion GTPases. Our current understanding of PD suggests that a-syn-mediated disruption of mitochondrial fusion/fission events may be a mechanism of neuronal toxicity. Nevertheless, this idea has never been tested. Mitochondrial fusion is thought to provide protection by facilitating the mixing mitochondrial contents, such as metabolites and mtDNA. Several observations of a-syn are in agreement with our hypothesis. First, brain tissue of PD patients and a-syn transgenic mice exhibit abnormal mitochondrial ultrastructure, respiratory complex I inhibition, and increased free radical production. In addition, overexpression of human a-syn in transgenic mice leads to dopaminergic synaptic loss. Furthermore, a-syn modulates membrane composition and forms pores similar to bacterial toxins. Intriguingly, Bax, a pro-cell death molecule of the Bcl-2 family that associates with the mitochondrial outer membrane, also has pore-forming activity and a structure similar to bacterial toxins. Recent publications show that Bax is a component of mitochondrial fission/fusion complexes in dying cells. Finally, a-syn cooperates in SNARE complex assembly that regulates exocytosis and membrane fusion. Mitofusins (Mfns) may mediate mitochondrial membrane fusion by a SNARE-like mechanism. Thus, it is conceivable that a-syn may interact with Mfns, similar to SNAREs. Dynamin-related GTPases regulate mitochondrial fission and fusion, important cellular processes that neurons must balance to maintain normal mitochondrial and synaptic activity. Dynamin-related protein 1 (Drp1) directs mitochondrial fission (division) and Mfn 1, 2 regulate mitochondrial fusion. Previous research has linked excessive mitochondrial fission to neurodegeneration and induction of mitochondrial fusion to the prevention of neuronal cell death. Bax co-localizes with Drp1 in fission complexes on mitochondria and regulates apoptotic mitochondrial fission. We believe that a-syn, like Bax, may interact with the Mfns or Drp1. Supporting this hypothesis is the observation that a-syn forms clusters on mitochondria that may constitute future or past fission sites. Mutant or abnormally folded a-syn may inhibit Mfn GTPase function and prevent mitochondrial fusion. Alternatively, a-syn may bind and activate Drp1, thereby promoting excessive fission. The consequences of such interactions might include the breakdown of long mitochondrial filaments into multiple, isolated fragments, chronic respiratory inhibition, increased free radical levels, impaired calcium buffering, energy decline, accumulation and manifestation of mtDNA mutations, and ultrastructural defects of mitochondria. Mitochondrial dysfunction, energy crisis, and oxidative stress would then cause loss of synapses, protein aggregation, and neuronal dysfunction and loss.

该子项目是利用资源的众多研究子项目之一由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持并且子项目的主要研究者可能是由其他来源提供的，包括其他 NIH 来源。子项目可能列出的总成本代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。我们正在使用 NCMIR 研究帕金森病 (PD) 和相关的神经退行性疾病。我们假设 α-突触核蛋白 (a-syn) 通过与线粒体裂变和融合 GTP 酶的异常相互作用诱导慢性线粒体裂变，从而引起神经变性。我们目前对 PD 的理解表明，a-syn 介导的线粒体融合/裂变事件的破坏可能是神经元毒性的机制。然而，这个想法从未被测试过。线粒体融合被认为通过促进混合线粒体内容物（例如代谢物和 mtDNA）来提供保护。 a-syn 的一些观察结果与我们的假设一致。首先，PD患者和a-syn转基因小鼠的脑组织表现出异常的线粒体超微结构、呼吸复合物I抑制和自由基产生增加。此外，转基因小鼠中人类α-syn的过度表达会导致多巴胺能突触丧失。此外，a-syn 调节膜组成并形成类似于细菌毒素的孔。有趣的是，Bax 是 Bcl-2 家族的一种促细胞死亡分子，与线粒体外膜结合，也具有成孔活性和类似于细菌毒素的结构。最近的出版物表明，Bax 是垂死细胞中线粒体裂变/融合复合物的组成部分。最后，a-syn 在 SNARE 复合体组装中合作，调节胞吐作用和膜融合。线粒体融合素 (Mfns) 可能通过类似 SNARE 的机制介导线粒体膜融合。因此，可以想象，a-syn 可能与 Mfns 相互作用，类似于 SNARE。动力相关 GTP 酶调节线粒体裂变和融合，这是神经元必须平衡以维持正常线粒体和突触活动的重要细胞过程。 Dynamin 相关蛋白 1 (Drp1) 指导线粒体分裂（分裂），Mfn 1, 2 调节线粒体融合。先前的研究已将线粒体过度裂变与神经变性联系起来，并将线粒体融合的诱导与预防神经元细胞死亡联系起来。 Bax 与 Drp1 共定位于线粒体的裂变复合物中，并调节细胞凋亡的线粒体裂变。我们相信 a-syn 与 Bax 一样，可能与 Mfns 或 Drp1 相互作用。支持这一假设的是观察到 a-syn 在线粒体上形成簇，可能构成未来或过去的裂变位点。突变或异常折叠的 a-syn 可能会抑制 Mfn GTP 酶功能并阻止线粒体融合。或者，a-syn 可能结合并激活 Drp1，从而促进过度裂变。这种相互作用的后果可能包括线粒体长丝分解成多个孤立的片段、慢性呼吸抑制、自由基水平升高、钙缓冲受损、能量下降、线粒体DNA突变的积累和表现以及线粒体的超微结构缺陷。线粒体功能障碍、能量危机和氧化应激会导致突触损失、蛋白质聚集以及神经元功能障碍和损失。