MITOCHONDRIAL FISSION AND NEURODEGENERATION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们正在使用NCMIR来研究帕金森病（PD）和相关的神经退行性疾病。我们假设α-突触核蛋白（α-syn）通过与线粒体分裂和融合GTP酶的异常相互作用诱导慢性线粒体分裂而引起神经变性。我们目前对PD的理解表明，α-syn介导的线粒体融合/分裂事件的破坏可能是神经元毒性的机制。然而，这一想法从未得到验证。线粒体融合被认为通过促进线粒体内容物（如代谢物和mtDNA）的混合来提供保护。对a-syn的几个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抑制和增加的自由基产生。此外，人a-syn在转基因小鼠中的过表达导致多巴胺能突触损失。此外，α-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家族的促细胞死亡分子，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分裂/融合复合物的组成部分。最后，α-syn在调节胞吐和膜融合的SNARE复合物组装中协作。线粒体融合素（Mitofusins，Mfns）可通过SNARE样机制介导线粒体膜融合。因此，可以想象a-syn可以与Mfn相互作用，类似于SNARE。动力蛋白相关的GTP酶调节线粒体分裂和融合，这是神经元必须平衡以维持正常线粒体和突触活性的重要细胞过程。动力蛋白相关蛋白1（Drp 1）指导线粒体分裂（分裂），Mfn 1，2调节线粒体融合。先前的研究已经将过度的线粒体分裂与神经变性联系起来，并将诱导线粒体融合与预防神经元细胞死亡联系起来。Bax与Drp 1共定位于线粒体上的裂变复合物中并调节凋亡线粒体裂变。我们相信a-syn和Bax一样，可能与Mfns或Drp 1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，这些簇可能构成未来或过去的裂变位点。突变或异常折叠的α-syn可抑制Mfn GT3功能并阻止线粒体融合。或者，α-syn可以结合并激活Drp 1，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，自由基水平增加，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将导致突触丢失、蛋白质聚集和神经元功能障碍和丧失。

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.