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

体内线粒体功能中分离区域特异性 α-syn 介导的机制

• 批准号: 10809994
• 负责人: Shermali Gunawardena
• 金额: $ 15.84万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-07 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10809994
• 关键词: Address; Affect; Axon; Biochemistry; Biology; Brain Diseases; C-terminal; Calcium; Clinical; Clinical Pathways; Computer Analysis; Coupled; Defect; Development; Disease; Disease Pathway; Drosophila genus; Dynamin; FDA approved; Functional disorder; Genes; Genetic; Genetic Models; Goals; Guanosine Triphosphate Phosphohydrolases; Health; Homeostasis; Inherited; Investigation; Knowledge; Lewy Bodies; Life; Link; Mediating; Membrane Potentials; Mission; Mitochondria; Mutation; N-terminal; Nerve Degeneration; Neurons; Organelles; Organism; Outcome; Oxidative Stress; Parkinson Disease; Pathologic; Pathology; Pathway interactions; Pharmaceutical Preparations; Physiological; Post-Translational Protein Processing; Process; Production; Proteins; Public Health; Quality Control; Regulation; Reporting; Research; Resolution; Risk Factors; Role; Shapes; Signal Transduction; Stress; Testing; Transgenic Animals; Transgenic Organisms; Trauma; Traumatic Brain Injury; United States National Institutes of Health; Whole Organism; Work; alpha synuclein; cell motility; cell type; cytochrome c; disability; dopaminergic neuron; in vivo; in vivo imaging; innovation; mitochondrial dysfunction; model organism; mutant; neuron loss; new therapeutic target; novel; oxidation; prevent; reduce symptoms; sporadic Parkinson' s Disease; synucleinopathy; targeted treatment; therapeutically effective

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.

帕金森病 (PD) 的特点是多巴胺能 (DA) 神经元的丧失和多巴胺能 (DA) 神经元的积累 路易体（LB），但潜在的致病机制尚不清楚。到目前为止，超过8个基因发生突变， 与许多不同的细胞途径有关的基因被确定可导致家族性帕金森病 (fPD)。然而，这些基因 也是散发性帕金森病 (sPD) 的危险因素，表明 fPD 和 sPD 都可能由于共同的病理原因而发生 逻辑机制。有趣的是，虽然大量的线粒体过程被认为受到 突变体 α-syn 是路易体中存在的蛋白质，但基本问题仍然是如何正常， 未突变的 α-syn 有助于线粒体稳态，以及突变、患病的 α-syn 如何导致线粒体- PD 中可见干燥功能障碍。这是因为一些报告显示了对比/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，为了解决这一知识差距，什么是 目前缺乏一种有凝聚力的策略来成功阐明α-的生理作用和病理作用 syn 在体内线粒体生物学中的应用。该提案的长期目标是了解 α-syn 介导的 线粒体功能障碍导致整个生物体中单个线粒体分辨率的PD。 该提案的中心假设是 α-syn 的特定区域在维持 mi- 方面具有关键作用。 软骨稳态。使用含有 N 端缺失或 C 端 PTM 缺失的转基因动物 系统蒸发散，将测试两个预测：1）α-syn 的 N 末端影响线粒体断裂途径， 2) α-syn 的 C 末端影响线粒体损伤/氧化机制。独特的策略 利用遗传模型生物体中信号线粒体的体内成像和计算分析（Dro- sophila）与生物化学相结合将被采用。其合理性在于，一旦 a-syn 介导的作用对 mi- 线粒体生物学被发现，针对有效治疗以维持线粒体的创新方法 可以启动干燥健康。目前PD还没有治愈方法。目前 FDA 批准的治疗方法仅减少 症状。这项工作对于分离区域特异性 α-syn 介导的机制具有重大影响 线粒体生物学，并获得有关共同途径如何促进 PD 病理学的知识，em- 在神经元损失和临床表现之前尽早确定靶向治疗的新途径 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，在器官中 主义;强调了不仅是帕金森病临床表现的潜在疾病途径，而且还包括其他疾病的临床表现 皮肤病，包括应激诱发的 TBI。拟议的研究意义重大，因为它有望垂直 极大地推进/扩展了关于如何启动 PD 的当前知识，极大地影响了当前的范式 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。