Investigating Mic60 as a novel gene therapy target for Parkinson's disease

研究 Mic60 作为帕金森病的新型基因治疗靶点

基本信息

批准号：
10575580
负责人：
Victor Steven Van Laar
金额：
$ 44.8万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-19 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10575580
关键词：
Address Affect Architecture Biodistribution Biogenesis Biological Availability Brain Cellular Stress Cellular Stress Response Data Development Disease Disease Progression Dopamine Dopaminergic Cell Dose Drosophila genus Elements Environment Etiology Event Functional disorder Gene Delivery Gene Transfer Genetic Genetic Models Goals Green Fluorescent Proteins Health Homeostasis Human Idiopathic Parkinson Disease In Vitro Lead Link Mediating Mitochondria Mitochondrial Proteins Modeling Molecular Conformation Movement Disorders Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Neurotransmitters Oxidative Stress Oxides PINK1 gene Parkin Parkinson Disease Parkinsonian Disorders Pathogenesis Pathogenicity Patients Phenotype Phosphorylation Play Poison Police Positioning Attribute Predisposition Proteins Rattus Research Respiration Risk Role Rotenone Safety Scaffolding Protein Signal Transduction Site-Directed Mutagenesis Stress Structural Protein Structure Substantia nigra structure Symptoms Testing Toxic effect Transgenes Up-Regulation Viral Viral Vector adeno-associated viral vector alpha synuclein base cell injury disease diagnosis dopamine toxicity dopaminergic neuron dosage driving force gene environment interaction gene therapy improved in vivo in vivo Model mitochondrial dysfunction motor behavior nervous system disorder neuron loss novel overexpression oxidation protective effect protein complex response stressor targeted treatment toxicant vector vector control

项目摘要

ABSTRACT At present, there are no treatments that hinder or halt the inexorable progression of Parkinson disease (PD), and there is a critical need to identify treatments that can alter the course of the disease. The use of gene-transfer therapy for neurodegeneration is a burgeoning field of research that has potential for directly addressing progressive neuron loss at the cellular level. The key is to identify genetic therapies that will restore cellular health and function, thereby altering the disease course. While the specific etiology of PD remains elusive, evidence suggests that early dysfunction of mitochondrial respiration and homeostasis play a major role in PD pathogenesis. The research focus of this proposal is to evaluate the potential of the essential mitochondrial structural protein Mic60, also known as mitofilin, as an avenue to develop novel, translatable neuroprotective strategies for PD. Mic60 is a crucial component of a larger mitochondrial protein complex vital for maintaining mitochondrial architecture and function, and loss of Mic60 can detrimentally affect mitochondrial homeostasis. Mic60 function is regulated by interactions with proteins associated with PD, mitochondrial PINK1 and Parkin, which police mitochondrial health and turnover. We previously found that cellular levels of Mic60 protein are decreased in the dopamine toxicity model of PD. We also have evidence that Mic60 abundance is lower in PD patient brain. Further, we found that Mic60 overexpression protects against PD-relevant toxicants, including the mitochondrial poison rotenone. We hypothesize that the observed protective effects of Mic60 overexpression occur via stabilization of mitochondrial function. We propose to investigate the potential of Mic60 as a gene therapy candidate for PD via the following aims: In Aim 1, we will determine the ideal dose and long-term safety of viral-mediated Mic60 overexpression in vivo for delivery to the substantia nigra. In Aim 2, we will test the neuroprotective effect of Mic60 overexpression in vivo in toxicity and genetic models of PD, to evaluate the potential of Mic60 as a targeted neuroprotective gene therapy for PD. Our ultimate goal is to build on our in vitro data and evaluate Mic60 for development of a novel, neuroprotective PD treatment. As mitochondrial dysfunction is a key contributor to PD and other neurodegenerative diseases, targeting mitochondrial integrity via Mic60 to improve neuronal health may yield a therapy for both genetic and sporadic forms of PD, and possibly other neurological disorders.

抽象的目前，尚无任何治疗方法可以阻止或阻止帕金森病 (PD) 的不可避免的进展，并且迫切需要找到可以改变疾病进程的治疗方法。基因转移的利用神经退行性疾病的治疗是一个新兴的研究领域，有可能直接解决细胞水平上进行性神经元丢失。关键是找到能够恢复细胞功能的基因疗法健康和功能，从而改变病程。虽然 PD 的具体病因仍不清楚，有证据表明线粒体呼吸和稳态的早期功能障碍在帕金森病中起重要作用发病。该提案的研究重点是评估必需线粒体的潜力结构蛋白 Mic60，也称为 mitofilin，作为开发新型可翻译神经保护剂的途径 PD 策略。 Mic60 是较大线粒体蛋白复合物的重要组成部分，对于维持线粒体至关重要结构和功能，并且 Mic60 的丢失会对线粒体稳态产生不利影响。麦克风60功能受到与 PD、线粒体 PINK1 和 Parkin 相关蛋白的相互作用的调节，这些蛋白负责监管线粒体健康和周转。我们之前发现 Mic60 蛋白的细胞水平在 PD的多巴胺毒性模型。我们还有证据表明 PD 患者大脑中的 Mic60 丰度较低。此外，我们发现 Mic60 过表达可以防止 PD 相关毒物，包括线粒体鱼藤酮有毒。我们假设观察到的 Mic60 过度表达的保护作用是通过线粒体功能的稳定。我们建议通过以下目标研究 Mic60 作为 PD 基因治疗候选者的潜力：目标 1，我们将确定病毒介导的 Mic60 体内过表达的理想剂量和长期安全性输送到黑质。在目标2中，我们将测试Mic60过表达的体内神经保护作用在 PD 的毒性和遗传模型中，评估 Mic60 作为靶向神经保护基因的潜力 PD 的治疗。我们的最终目标是基于我们的体外数据并评估 Mic60 以开发一种新颖的、神经保护性PD治疗。由于线粒体功能障碍是 PD 和其他疾病的关键因素神经退行性疾病，通过 Mic60 靶向线粒体完整性以改善神经元健康可能为遗传性和散发性帕金森病以及可能的其他神经系统疾病提供治疗方法。