MITOCHONDRIAL FISSION AND NEURODEGENERATION

线粒体裂变和神经变性

• 批准号: 7957597
• 负责人: Ella R Bossy-Wetzel
• 金额: $ 4.99万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7957597
• 关键词: Agreement; Alpha-Synuclein transgenic mouse; Apoptotic; Bacterial Toxins; Binding; Buffers; Calcium; Cell Death; Cell physiology; Cells; Chronic; Complex; Computer Retrieval of Information on Scientific Projects Database; Defect; Dynamin; Equilibrium; Event; Exhibits; Exocytosis; Family; Filament; Free Radicals; Funding; Future; Grant; Guanosine Triphosphate Phosphohydrolases; Image Analysis; Institution; Link; Mediating; Membrane; Membrane Fusion; Mitochondria; Mitochondrial DNA; NADH dehydrogenase (ubiquinone); Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Outer Mitochondrial Membrane; Oxidative Stress; Parkinson Disease; Patients; Prevention; Production; Proteins; Publications; Research; Research Personnel; Resources; SNAP receptor; Site; Source; Structure; Synapses; Testing; Transgenic Mice; United States National Institutes of Health; alpha synuclein; brain tissue; mitochondrial DNA mutation; mitochondrial dysfunction; mitochondrial membrane; mutant; neuron loss; neurotoxicity; overexpression; prevent; protein aggregation; respiratory; synuclein, alpha (non A4 component of amyloid precursor) protein, human

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 我们正在使用NCMIR研究帕金森氏病（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GTPases诱导慢性线粒体裂变来引起神经退行性。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毒性的机制。但是，这个想法从未经过测试。线粒体融合被认为可以通过促进混合线粒体含量（例如代谢产物和mtDNA）来提供保护。 A-Syn的几种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抑制作用，并增加了自由基产生。另外，转基因小鼠中人A-Syn的过表达导致多巴胺能突触损失。此外，A-Syn调节膜组成并形成类似细菌毒素的孔。有趣的是，Bax是Bcl-2家族的亲细胞死亡分子，它与线粒体外膜相关，也具有孔形成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在调节胞胞菌病和膜融合的军鼓复合物组件中合作。丝脂素（MFN）可以通过类似工资般的机制介导线粒体膜融合。因此，可以想象A-Syn可能与MFN相互作用，类似于SNARES。与动力蛋白相关的GTP酶调节线粒体裂变和融合，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。与动力蛋白相关的蛋白1（DRP1）指导线粒体裂变（分裂）和MFN 1，2调节线粒体融合。先前的研究已将过度的线粒体裂变与神经变性和线粒体融合的诱导与预防神经元细胞死亡有关。 BAX与DRP1在线粒体上的裂变复合物中共定位，并调节凋亡线粒体裂变。我们认为，像Bax一样的A-Syn可能会与MFN或DRP1相互作用。支持这一假设的是，A-Syn在线粒体上形成可能构成未来或过去裂变位点的线粒体簇。突变体或异常折叠的A-Syn可能会抑制MFN GTPase功能并防止线粒体融合。或者，A-Syn可以结合并激活DRP1，从而促进过度的裂变。这种相互作用的后果可能包括将长的线粒体细丝分解为多个孤立的片段，慢性呼吸抑制，自由基水平增加，钙缓冲受损，能量下降，MTDNA突变的积累和表现，MTDNA突变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将导致突触丧失，蛋白质聚集以及神经元功能障碍和损失。