MITOCHONDRIAL FISSION AND NEURODEGENERATION

线粒体裂变和神经变性

• 批准号: 7722407
• 负责人: Ella R Bossy-Wetzel
• 金额: $ 3.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7722407
• 关键词: Agreement; Alpha-Synuclein transgenic mouse; Apoptotic; Bacterial Toxins; Binding; Buffers; Calcium; Cell Death; Cell physiology; Cells; Chromosome Pairing; Chronic; Complex; Computer Retrieval of Information on Scientific Projects Database; Defect; Disruption; Dynamin; Equilibrium; Event; Exhibits; Exocytosis; Family; Filament; Free Radicals; Funding; Future; Grant; Guanosine Triphosphate Phosphohydrolases; Institution; Link; Localized; 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; Protein Overexpression; Proteins; Publications; Research; Research Personnel; Resources; SNAP receptor; Site; Source; Structure; Synapses; Testing; Thinking; Transgenic Mice; United States National Institutes of Health; alpha synuclein; brain tissue; mitochondrial DNA mutation; mitochondrial dysfunction; mitochondrial membrane; mutant; neuron loss; neurotoxicity; 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.

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