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）的特征在于多巴胺能（DA）神经元的损失和多巴胺能神经元的积聚。 路易体（LB），但潜在的致病机制是未知的。到目前为止，超过8个基因的突变， 参与许多不同细胞途径的PD被鉴定为引起家族性PD（fPD）。然而，这些基因 也是散发性PD（sPD）的危险因素，这表明fPD和sPD都可能是由于共同的病理因素引起的。 逻辑机制。有趣的是，虽然大量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，基本的问题仍然存在， 未突变的α-syn有助于线粒体内稳态，以及突变的患病α-syn如何引起线粒体内稳态。 PD中观察到的排尿功能障碍。这是因为几份报告显示了对比/冲突的结果， 使用的细胞类型和检测的α-syn表达水平。因此，要解决这一知识差距， 目前缺乏的是一个连贯的战略，成功地解开生理从病理作用的α- syn在体内线粒体生物学中的应用。这项提案的长期目标是了解α-syn-mediated 线粒体功能障碍在整个生物体中单个线粒体的分解时有助于PD。 这个建议的中心假设是，α-syn的特定区域在维持mi中起着关键作用。 拓扑内稳态使用含有N-末端缺失或C-末端PTM缺失的转基因动物， 因此，将检验两个预测：1）α-syn的N-末端影响线粒体片段化途径， 2）α-syn的C-末端影响线粒体损伤/氧化机制。一个独特的战略， 利用遗传模型生物体（Dro， sophila）与生物化学相结合。合理的是，一旦a-syn介导的作用在mi- 肿瘤生物学被发现，创新的方法来靶向有效的治疗，以维持mitochon- 就可以启动Drial Health。目前还没有治疗PD的方法。目前FDA批准的治疗方法只能减少 症状这项工作对分离区域特异性α-syn-mediated机制具有重要影响， 线粒体生物学，并获得关于共同途径如何有助于PD病理学的知识， 在神经元丢失和两者的临床表现之前早期强调靶向治疗的新途径 fPD/sPD。这项工作是创新的，因为它代表了一个新的/实质性的脱离现状; 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， 突出了一个潜在的疾病途径，不仅是PD的临床表现，而且还有其他综合征， 包括应激诱发的TBI。这项研究意义重大，因为它有望垂直- 彻底推进/扩展关于PD如何启动的现有知识，极大地影响当前的范例， 显著地推动了针对α-syn介导的线粒体缺陷的新型修饰剂的开发。