MITOCHONDRIAL FISSION AND NEURODEGENERATION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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(a-syn)通过与线粒体分裂和融合GTP酶的异常相互作用而引起慢性线粒体分裂，从而导致神经退行性变。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一个机制。然而，这一想法从未被检验过。线粒体融合被认为通过促进线粒体内容物(如代谢物和线粒体DNA)的混合来提供保护。对a-syn的几个观察结果与我们的假设是一致的。首先，帕金森病患者和a-syn转基因小鼠的脑组织表现出线粒体超微结构异常，呼吸复合体I抑制，自由基产生增加。此外，在转基因小鼠中过表达人a-syn会导致多巴胺能突触丢失。此外，a-syn还调节膜成分并形成类似细菌毒素的毛孔。有趣的是，Bax，一种与线粒体外膜相关的Bcl-2家族的促细胞死亡分子，也具有成孔活性和类似细菌毒素的结构。最近的文献表明，Bax是濒死细胞中线粒体分裂/融合复合体的组成部分。最后，a-syn在调节胞吐和膜融合的SNARE复合体组装中协同作用。丝裂原蛋白(Mitofusins，Mfns)可能通过一种类似陷阱的机制来介导线粒体膜融合。因此，可以想象a-SYN可以与MFN相互作用，类似于陷阱。动力蛋白相关的GTP酶调节线粒体的分裂和融合，神经元必须平衡这些重要的细胞过程才能维持正常的线粒体和突触活动。动力蛋白相关蛋白1(Dynamin-Related Protein 1，DRp1)指导线粒体分裂，MFN1、2调控线粒体融合。以前的研究已经将过度的线粒体分裂与神经退行性变联系起来，并将线粒体融合的诱导与防止神经细胞死亡联系起来。Bax与Drp1共同定位于线粒体的分裂复合体中，并调控线粒体的凋亡分裂。我们认为，a-syn和Bax一样，可能与Mfn或Drp1相互作用。支持这一假设的是观察到的a-syn在线粒体上形成的簇，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a-syn可能会抑制MFN GTP酶功能，阻止线粒体融合。或者，a-syn可以结合并激活Drp1，从而促进过度分裂。这种相互作用的后果可能包括线粒体长丝断裂成多个孤立的片段，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会导致突触丢失、蛋白质聚集，以及神经元功能障碍和丢失。

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.