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.

帕金森氏病（PD）的特征是多巴胺能（DA）神经元的丧失和积累 路易尸体（LB），但潜在的严重机制尚不清楚。到目前为止，超过8个基因的突变， 在许多不同的细胞途径中实施以引起家族性PD（FPD）。但是，这些基因 也是散发性PD（SPD）的危险因素，这表明FPD和SPD可能由于常见的病原 逻辑机制。有趣的是，虽然众多线粒体过程被认为受到 突变体α-syn是在路易体中呈现的蛋白质，基本问题仍然保持正常状态， 未分解的α-syn有助于线粒体稳态以及突变体，患病的α-Syn如何引起线粒体 钻机功能障碍在PD中可见。这是因为几份报告显示了对比/相互冲突的结果 所使用的细胞类型和测试的α-Syn表达水平。因此，要解决这个差距 目前缺乏的是一种凝聚力的策略，可以成功地从α-的病理作用中揭示物理 线粒体生物学中的同步体内体内。该提案的长期目标是了解α-Syn介导的 线粒体功能障碍在整个生物体中单个线粒体的分辨率下有助于PD。 该提议的核心假设是α-Syn的特定区域在维持Mi-i-i-i-i-a-syn中具有关键作用 toendrial稳态。使用含有N末端缺失或C末端PTM DELE-的转基因动物 将测试两个预测：1）α-Syn的N末端影响线粒体碎片途径， 2）α-Syn的C端会影响线粒体损伤/氧化机制。一个独特的策略 利用遗传模型生物中信号线粒体的体内成像和计算分析 将使用Sophila）加上生物化学。理性的是，一旦A-syn介导的角色 图形生物学是针对有效疗法的创新方法，以维持线形 可以启动钻井健康。目前没有PD治疗方法。当前FDA批准的治疗只会减少 症状。这项工作对隔离区域的特定α-Syn介导的机制具有重大影响 线粒体生物学，并获得有关公共途径如何有助于PD病理学的知识 在神经元丧失和两者的临床表现之前，早期靶向治疗的新颖途径 FPD/SPD。这项工作具有创新性，因为它代表了与现状的新/实质性不同。 ap- 隔离A-Syn在体内线粒体健康中的物理和病理作用的方法，在器官中 主义;强调了潜在的疾病途径，不仅是PD的临床表现，还强调了其他Synu- 克氏病，包括应力诱导的TBI。拟议的研究很重要，因为预计 呼叫Advance/Aftim Afturn有关PD启动的当前知识，从而极大地影响当前范例 驱动地推动新的修饰剂针对A-Syn介导的线粒体缺陷的开发。