TMEM230 and Neurodegeneration in Parkinson's Disease

TMEM230 与帕金森病的神经退行性变

• 批准号: 10705592
• 负责人: xugang xia
• 金额: $ 34.66万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705592
• 关键词: 20p; Affect; Aging; Animal Model; Bioinformatics; C-terminal; Cell Culture Techniques; Cell Death; Cell physiology; Chromosomes; DNA Sequence Alteration; DNA Sequence Rearrangement; Development; Diagnosis; Disease; Disease Progression; Dopamine; Elderly; Family; Genes; Genetic; Genetic Polymorphism; Human; Immunoprecipitation; Impairment; Knock-in; Knock-out; Link; Midbrain structure; Molecular; Molecular Chaperones; Monitor; Mutation; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nucleotides; Paper; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Penetrance; Phenotype; Physiological; Pilot Projects; Point Mutation; Process; Proteins; Proteomics; Rat Transgene; Rattus; Reporting; Research; Role; Transgenic Organisms; Variant; biomarker identification; cohort; disease phenotype; dopaminergic neuron; effective therapy; exome sequencing; functional loss; gene discovery; genetic linkage analysis; genetic variant; genome sequencing; genome-wide linkage; invention; mutant; neuron loss; neuronal survival; neuroprotection; next generation sequencing; novel; overexpression; promoter; reuptake; segregation; targeted sequencing; therapeutic effectiveness; tool; whole genome

Parkinson’s disease (PD) is a common neurodegenerative disease characterized by progressive degeneration of dopaminergic neurons in the midbrain. At present, PD is incurable. A roadblock halting development of effective therapy for PD is the limited understanding of PD pathogenesis. While most PD cases are sporadic without an ascertained cause, about 10% of PD cases are likely caused by mutation of a known or unknown gene. Genetic clues not only help define the molecular pathways leading to neurodegeneration but also help identify biomarkers for monitoring disease progression and therapeutic effectiveness. Compared to the other neurodegenerative diseases, genetic discovery for PD is significantly deferred. One reason for deferred genetic discovery in PD is the incomplete penetrance of disease phenotypes in PD and it is particularly true for late-onset PD. A compelling need for PD research is identifying and validating the genes segregating with late-onset PD. Recently the new gene TMEM230 was reported to cosegregate with disease in a large family affected by late-onset PD. Once after a novel disease gene is identified, enormous efforts are required to validate the authenticity of the pathogenic role of the mutant gene in the disease. First, genetic variants cosegregating with the disease must be verified in independent families afflicted with the disease. Second, disease phenotypes observed in patients carrying the genetic variant must be reproduced in animal models expressing the disease-associated mutation. Third, mechanistic studies must be fulfilled to reveal how the disease-linked mutation impairs cellular functions and thus to determine how these new mechanisms are integrated into existing pathways leading to cell death in the disease. Validating process often takes many years to consolidate the authenticity of a genetic mutation after a disease gene is identified. In the proposed studies, we will take comprehensive approaches to validating the pathogenic role of TMEM230 mutation in late-onset PD by using both cell culture and animal models. Upon completion, our study will determine the effect of TMEM230 mutation on neuronal functions at both systemic and molecular levels.

帕金森病（PD）是一种常见的神经退行性疾病，其特征是进行性退化 中脑的多巴胺能神经元。目前，PD是无法治愈的。阻碍发展的障碍 PD的有效治疗方法在于对PD发病机制的了解有限。虽然大多数 PD 病例都是散发的 在没有确定原因的情况下，大约 10% 的 PD 病例可能是由已知或未知的突变引起的 基因。遗传线索不仅有助于确定导致神经退行性变的分子途径，还有助于 确定用于监测疾病进展和治疗效果的生物标志物。与其他相比 神经退行性疾病，帕金森病的基因发现被大大推迟。延迟遗传的原因之一 PD 的一个发现是 PD 疾病表型的不完全外显，对于晚发性 PD 尤为如此。 PD 研究的迫切需要是识别和验证与晚发型分离的基因 PD。最近，据报道，新基因 TMEM230 在一个受感染的大家族中与疾病共分离。 迟发性PD。一旦发现了新的疾病基因，就需要付出巨大的努力来验证该基因 突变基因在疾病中致病作用的真实性。首先，遗传变异与 必须在患有该疾病的独立家庭中验证该疾病。二、疾病表型 在携带遗传变异的患者中观察到的结果必须在表达疾病相关突变的动物模型中重现。第三，必须完成机制研究以揭示与疾病相关的突变是如何发生的。 损害细胞功能，从而确定如何将这些新机制整合到现有的 导致疾病中细胞死亡的途径。验证过程通常需要很多年才能巩固 确定疾病基因后基因突变的真实性。在拟议的研究中，我们将采取 验证 TMEM230 突变在迟发性 PD 中的致病作用的综合方法 细胞培养和动物模型。完成后，我们的研究将确定 TMEM230 突变的影响 系统和分子水平上的神经元功能。