Isolating region specific α-syn-mediated mechanisms in mitochondrial function in vivo

帕金森病(PD)的特征是多巴胺(DA)能神经元的丢失和脑组织中 路易小体(Lb)，但其潜在的致病机制尚不清楚。到目前为止，超过8个基因的突变， 许多不同的细胞通路参与了导致家族性帕金森病(FPD)的研究。然而，这些基因 也是散发性帕金森病(SPD)的危险因素，提示FPD和SPD都可能是由共同的病理机制引起的。 逻辑机制。有趣的是，虽然过多的线粒体过程被认为是受 突变的α-SYN，存在于路易体中的蛋白质，基本的问题仍然是如何正常， 未突变的α-SYN有助于线粒体的动态平衡，以及突变的、患病的α-SYN如何导致有丝分裂- 帕金森病患者出现神经功能障碍。这是因为多个报告显示了不同/冲突的结果，具体取决于 使用的细胞类型和测试的α-SYN表达水平。因此，要解决这个认识上的差距， 目前缺乏一种连贯的策略来成功地将α的生理作用从病理作用中解开- SYN在体内线粒体生物学中的作用。该提案的长期目标是了解α-SYN如何调解 线粒体功能障碍在整个生物体中单个线粒体的分解时导致帕金森病。 这一建议的中心假设是α-SYN的特定区域在维持MI-SYN的过程中起着关键作用。 线粒体动态平衡。利用含有N端缺失或C端PTM缺失的转基因动物- 两个预测将被检验：1)α-SYN的N-末端影响线粒体的碎裂途径， 2)α-SYN的C末端影响线粒体的损伤/氧化机制。一种独特的战略 利用遗传模式生物体内信号线粒体的成像和计算分析。 苍蝇)与生物化学相结合。合理的是，一旦a-syn介导的角色在MI- 线粒体生物学是被发现的，针对有效治疗的创新方法，以维持线粒体- 可以启动日常健康。目前还没有治疗帕金森病的方法。目前FDA批准的治疗方法仅减少了 症状。这项工作对分离区域特异性α-SYN介导的机制具有重大影响。 线粒体生物学，以及获得关于共同途径如何促进帕金森病病理的知识，EM- 在神经元丢失和两者的临床表现之前就重视靶向治疗的新途径 FPD/SPD。这项工作具有创新性，因为它代表了对现状的新的/实质性的偏离；美联社- 分离a-syn在体内线粒体健康中的生理和病理作用的方法 ISM；强调一个潜在的疾病途径，不仅是帕金森病的临床表现，也是其他综合征的临床表现。 神经官能症，包括应激性脑损伤。这项拟议的研究意义重大，因为它有望证实-- Cally推进/扩展了关于PD如何启动的现有知识，对当前的范式产生了重大影响 极大地推动了针对a-syn介导的线粒体缺陷的新型修饰剂的开发。

Parkinson's disease (PD) is characterized by the loss of dopaminergic (DA) neurons and the accumulation of Lewy Bodies (LB), but the underlying causative mechanism is unknown. So far, mutations in more than 8 genes, implicated in many different cellular pathways are identified to cause familial PD (fPD). However, these genes are also risk factors for sporadic PD (sPD), suggesting that both fPD and sPD could arise due to common patho- logical mechanisms. Interestingly, while a plethora of mitochondrial processes are thought to be influenced by mutant α-syn, the protein that is present in Lewy Bodies, fundamental questions still remain as to how normal, unmutated α-syn contributes to mitochondrial homeostasis and how mutant, diseased α-syn cause mitochon- drial dysfunction seen in PD. This is because several reports show contrasting/conflicting results depending on the cell types used and the α-syn expression level tested. Therefore, to address this gap in knowledge what is currently lacking is a cohesive strategy to successfully unravel the physiological from the pathological role of α- syn in mitochondrial biology in vivo. The long-term goal of this proposal is to understand how α-syn-mediated mitochondrial dysfunction contributes to PD at the resolution of a single mitochondrion in a whole organism. The central hypothesis of this proposal is that particular regions of α-syn have critical roles in maintaining mi- tochondrial homeostasis. Using transgenic animals containing N-terminal deletions or C-terminal PTM dele- tions, two predictions will be tested: 1) the N-terminus of α-syn affects mitochondrial fragmentation pathways, and 2) the C-terminus of α-syn affects mitochondrial damage/oxidation mechanisms. A unique strategy that utilizes in vivo imaging and computation analysis of signal mitochondrion in a genetic model organism (Dro- sophila) coupled with biochemistry will be employed. The rational is that once the a-syn-mediated roles on mi- tochondrial biology are uncovered, innovative approaches to target effective therapeutics to maintain mitochon- drial health can be initiated. Currently there are no cures for PD. Current FDA approved treatments only reduce symptoms. This work has significant impact on isolating the region specific α-syn-mediated mechanisms on mitochondrial biology, and obtaining knowledge on how a common pathway contributes to PD pathology, em- phasizing a novel avenue for targeted therapeutics early before neuronal loss and clinical manifestation of both fPD/sPD. This work is innovative as it represents a new/substantive departure from the status quo; the ap- proach of isolating the physiological and pathological roles of a-syn in mitochondrial health in vivo, in an organ- ism; highlighting a potential disease pathway for the clinical manifestation of not just PD, but also other synu- cleinopathies, including stress induced TBI. The proposed research is significant, because it is expected to verti- cally advance/expand current knowledge on how PD is initiated, considerably impacting current paradigms to dramatically propel the development of novel modifiers against a-syn-mediated mitochondrial defects.