TMEM230 and Neurodegeneration in Parkinson's Disease

TMEM230 与帕金森病的神经退行性变

• 批准号: 10268170
• 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/10268170
• 关键词: 20p; Affect; Aging; Animal Model; Bioinformatics; Biological Markers; C-terminal; Cell Culture Techniques; Cell Death; Cell physiology; Chromosomes; DNA Sequence Alteration; Development; Diagnosis; Disease; Disease Progression; Dopamine; Elderly; Family; Genes; Genetic; Genetic Polymorphism; Genomics; 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; Rattus; Reporting; Research; Role; Therapeutic; Transgenic Organisms; Variant; cohort; disease phenotype; dopaminergic neuron; effective therapy; exome; exome sequencing; functional loss; genetic linkage analysis; genetic variant; genome sequencing; genome-wide linkage; invention; mutant; neuron loss; next generation sequencing; novel; overexpression; promoter; reuptake; 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.

帕金森病是一种常见的以进行性变性为特征的神经退行性疾病 多巴胺能神经元的数量目前，PD是无法治愈的。一个阻碍发展的路障 有效治疗PD的关键是对PD发病机制的有限认识。虽然大多数PD病例是散发的， 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， 鉴定用于监测疾病进展和治疗有效性的生物标志物。相比其他 在神经退行性疾病中，PD的遗传发现被显著推迟。遗传延迟的一个原因是 在PD中的发现是PD中疾病表型的不完全表达，并且对于晚发型PD尤其如此。帕金森病研究的迫切需要是鉴定和验证与晚发性帕金森病相关的基因。 警局最近，新基因TMEM230被报道在一个大家族中与疾病共分离， 迟发性帕金森病一旦发现了新的疾病基因，就需要付出巨大的努力来验证其有效性。 突变基因在疾病中致病作用的真实性。首先，遗传变异与 这种疾病必须在患有这种疾病的独立家庭中得到证实。二、疾病表型 在携带遗传变异的患者中观察到的突变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，以揭示疾病相关突变是如何发生的。 损害细胞功能，从而确定这些新的机制是如何整合到现有的 导致疾病中细胞死亡的途径。验证过程通常需要多年时间来巩固 鉴定疾病基因后基因突变的真实性。在研究中，我们将 使用综合方法验证TMEM 230突变在晚发性PD中的致病作用 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， 对神经元功能的影响