Genetic Movement Disorders: Etiologies and Pathogeneses

遗传运动障碍：病因和发病机制

• 批准号: 10486505
• 负责人: CYRUS P ZABETIAN
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10486505
• 关键词: Acceleration; Affect; Aging; Ataxia; Autoimmunity; Autophagocytosis; Autopsy; Basic Science; Biochemical Pathway; Biological; Biological Models; Birds; Brain; Candidate Disease Gene; Categories; Chorea; Chromosome Mapping; Clinical; Collaborations; Collection; Copy Number Polymorphism; DNA; Data; Data Set; Development; Diagnosis; Disease; Drosophila genus; Dystonia; Dystonic Disorder; Etiology; Evaluation; Family; Family member; Gene Expression Profiling; Genes; Genetic; Genetic Diseases; Genetic Research; Genomic Segment; Genotype; Goals; Health; Hereditary Dystonia; Hereditary Spastic Paraplegia; Heritability; Human; Idiopathic Parkinson Disease; Impairment; In Vitro; Individual; Inherited; Intervention; Knowledge; Lead; Massive Parallel Sequencing; Mission; Modeling; Molecular; Movement; Movement Disorders; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Pancytopenia; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Preventive; Productivity; Proteins; Research Personnel; Research Project Grants; Research Proposals; Resolution; Resources; Role; SNP array; Sampling; Spastic Paraplegia; Syndrome; Tauopathies; Techniques; Technology; Tissues; United States; Validation; Variant; Veterans; analytical method; bioinformatics tool; biomarker panel; causal variant; cell type; cost; diagnostic accuracy; exome; exome sequencing; fascinate; gene discovery; gene product; genetic risk factor; genetic technology; genome sequencing; identity by descent; improved; in vivo Model; induced pluripotent stem cell; interest; member; military veteran; mutant; nervous system disorder; neurogenetics; neuronal survival; next generation sequencing; parkinson' s disease registry; pharmacologic; proband; protein complex; protein protein interaction; recruit; repository; research study; sample collection; spasticity; stem cell model; success; synucleinopathy; targeted treatment; tau Proteins; trafficking; transcriptome sequencing; transmission process; vacuolar H+-ATPase

This application proposes to identify molecular etiologies of heritable movement disorders and elucidate effects of pathogenic variants as important steps towards improving diagnoses and development of targeted therapies. The categories of disease studied in this project, including Parkinson’s disease (PD) and related syndromes, ataxias, spastic paraplegias, and choreiform or dystonic disorders, are all genetically heterogeneous. We have identified the underlying genes for multiple movement disorders, some of which are a focus in this proposal, and initiated studies on their pathogeneses. Many more contributing genes remain to be discovered. We propose to 1) continue to ascertain and characterize individuals and families with genetically unattributed movement disorders; 2) use state-of-art gene mapping and next-generation sequencing technologies to discover new genes for movement disorders; and 3) investigate pathogenic mechanisms of variants using patient tissues, patient-derived stem cell models, and Drosophila models. The proposal builds on established synergistic collaborations and multifaceted clinical, pathological, basic science, and translational expertise of the Investigators and Collaborators. It also leverages the invaluable resources of two large collections of samples ascertained, extensively characterized, and extended over 30 years (Neurogenetics and PD repositories). Our approach to disease gene identification combines traditional linkage or identity-by-descent (IBD) analysis to identify genomic regions shared by all affected family members, together with exome or genome sequencing and copy number variation (CNV) analysis to identify variants in the linkage/IBD region shared by affected relatives. Advances in statistical genetics and use of denser marker panels make it possible to perform such studies in smaller families and more powerful bioinformatics tools offer a stepwise filtering approach to prioritize likely pathogenic variants for further study. Cosegregation of a variant with disease in single families and identification of mutations in the same gene in other families and large publicly available datasets of sporadic cases with the same disorder provide validation that the gene is responsible for the disease. Disease pathogenesis can then be investigated through mechanistic studies. This approach has led to our documented record of consistent productivity in parsing genetic neurologic disorders. For functional studies, we focus on the RAB39B α-synucleinopathy, the ATP6AP2 tauopathy, and SAMD9L ataxia, pancytopenia and autoimmunity syndrome, three disorders whose causative genes we discovered, and GBA, which is the strongest known genetic risk factor for idiopathic PD. These four genes participate in endolysosomal trafficking and autophagy, pathways frequently implicated in PD and other neurodegenerative disorders. By analysis of gene expression in human autopsy brain samples, we will identify vulnerable cell types and characterize region-specific changes that drive pathology. Neural and glial cells reprogrammed from induced pluripotent stem cells (iPSC) of patients will be used to investigate effects of pathogenic variants in each of these genes, such as a connection between deficiency in ATP6AP2/V-ATPase function, impaired autophagy, and turnover of aggregation-prone tau protein. Autophagy will be pharmacologically induced to explore mitigation of tau pathology and improve neuronal survival. Drosophila and iPSC models will be used to investigate how RAB39B and ATP6AP2 proteins interact with GBA and how pathogenic variants in RAB39B, ATP6AP2, and SAMD9L influence endolysosomal trafficking. Beyond the implication of gene discovery for patients who suffer from a particular disorder, each new gene contributes to our understanding of the complex protein-protein interactions involved in neurodegeneration. Furthermore, from their biochemical pathways and protein complexes each new gene can uncover additional candidate genes for the disorders that can also be considered as targets for intervention.

该应用建议识别可遗传运动障碍的分子病因并阐明效果 致病变体作为改善诊断和开发目标的重要步骤 疗法。该项目中的疾病研究类别，包括帕金森氏病（PD）和相关 综合征，共济失调，痉挛性截瘫和浮游或畸形疾病都是遗传学的 异质。我们已经确定了多种运动障碍的潜在基因，其中一些是一个 专注于该提案，并开始对其病原体进行研究。更多的贡献基因仍然是 发现。我们建议1）继续确定和表征一个普遍的个人和家庭 未归因于运动障碍； 2）使用最先进的基因映射和下一代测序 发现运动障碍的新基因的技术； 3）研究 使用患者组织，患者来源的干细胞模型和果蝇模型的变体。提案建立 关于既定的协同合作以及多方面的临床，病理，基础科学和 研究人员和合作者的翻译专业知识。它还利用了两个的宝贵资源 大量样品确定，广泛表征并延长了30年 （神经遗传学和PD存储库）。 我们疾病基因鉴定组合的方法传统连锁或逐渐认同（IBD） 分析以识别所有受影响家庭成员共享的基因组区域以及外显子组或基因组 测序和拷贝数变化（CNV）分析，以识别链接/IBD区域中共享的变体 受影响的亲戚。统计遗传学的进步和密集标记面板的使用使得 在较小的家庭和更强大的生物信息学工具中进行此类研究，提供逐步过滤 优先级可能的致病性变异的方法进行进一步研究。疾病变体的cosegregation 单身家庭和其他家庭中同一基因中突变的鉴定以及大型公开可用 患有相同疾病的零星病例的数据集提供了基因负责的验证 疾病。然后可以通过机械研究来研究疾病发病机理。这种方法引起了 据我们记录在解析遗传神经系统疾病中一致生产力的记录。 在功能研究中，我们专注于RAB39Bα-突触核病，ATP6AP2 tauopathy和SAMD9L 共济失调，全年症和自身免疫综合症，三种疾病，我们发现的灾难性基因，以及 GBA，这是特发性PD的强烈已知遗传危险因素。这四个基因参与 内溶性贩运和自噬，经常在PD和其他神经退行性中实施 疾病。通过分析人尸检大脑样品中的基因表达，我们将识别脆弱的细胞 类型和表征驱动病理学的区域特异性变化。神经和神经胶质细胞从 诱导的多能干细胞（IPSC）将用于研究致病变异的影响 这些基因中的每一个，例如ATP6AP2/V-ATPase功能中缺乏症之间的连接损害 自噬和容易发生的tau蛋白的营业额。自噬将被药物诱导 探索缓解TAU病理学并改善神经元存活。果蝇和IPSC模型将用于 研究RAB39B和ATP6AP2蛋白如何与GBA相互作用以及Rab39b中的致病变异 ATP6AP2和SAMD9L影响内溶性贩运。 除了基因发现对患有特定疾病的患者的影响之外，每个新基因 有助于我们对神经变性涉及的复杂蛋白质蛋白相互作用的理解。 此外，从它们的生化途径和蛋白质复合物中，每个新基因都可以发现更多 疾病的候选基因，也可以被视为干预目标。