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），但目前尚不清楚其潜在致病机制，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)。 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 逻辑机制是负面的，而大量的线粒体过程被认为受到影响。 突变体 α-syn 是路易体中存在的蛋白质，但基本问题仍然存在，即如何正常， 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 中出现的干燥功能障碍是因为一些报告显示了对比/冲突的结果，具体取决于不同的情况。 因此，要解决这一知识空白是什么。 目前缺乏的是一个有凝聚力的策略来成功地阐明α-的生理作用和病理作用 syn 在体内线粒体生物学中的作用 该提案的长期目标是了解 α-syn 是如何介导的。 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。 该提案的中心区域假设是，α-syn 的特殊性在维持 mi- 方面具有关键作用。 使用含有 N 末端缺失或 C 末端 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/氧化机制的独特策略。 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）与生物化学相结合的原理是，一旦a-syn介导的作用对mi-。 线粒体生物学被发现，是针对维持线粒体的有效疗法的创新方法 目前 FDA 批准的治疗方法只能减轻帕金森病的症状。 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 是一项创新，因为它代表了对现状的新的/实质性的偏离； 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，也是其他疾病的潜在疾病途径。 包括应激诱发的 TBI 在内的癌症疾病，这项研究意义重大，因为它预计会导致脑损伤。 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。