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.

该申请旨在确定遗传性运动障碍的分子病因并阐明其影响 致病变异是改善诊断和开发靶向药物的重要步骤 疗法。本项目研究的疾病类别，包括帕金森病（PD）及相关疾病 综合征、共济失调、痉挛性截瘫以及舞蹈样或肌张力障碍都是遗传性的 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 重点关注这一建议，并启动了对其发病机制的研究。还有更多的贡献基因有待研究 发现了。我们建议 1) 继续确定和表征具有遗传基因的个人和家庭 不明原因的运动障碍； 2) 使用最先进的基因图谱和下一代测序 发现运动障碍新基因的技术； 3）研究致病机制 使用患者组织、患者来源的干细胞模型和果蝇模型的变体。该提案构建 建立协同合作和多方面的临床、病理、基础科学和 研究人员和合作者的翻译专业知识。它还利用了两个宝贵的资源 大量样本被确定、广泛表征并延续了 30 多年 （神经遗传学和 PD 存储库）。 我们的疾病基因识别方法结合了传统的连锁或血统同一性 (IBD) 分析以确定所有受影响的家庭成员共享的基因组区域，以及外显子组或基因组 测序和拷贝数变异 (CNV) 分析，以识别 共享的连锁/IBD 区域中的变异 受影响的亲属。统计遗传学的进步和更密集标记组的使用使得有可能 在较小的家庭中进行此类研究，更强大的生物信息学工具提供了逐步过滤 优先考虑可能的致病变异以供进一步研究的方法。与疾病相关的变体的共分离 单个家族以及其他家族和大型公开可用的同一基因突变的鉴定 具有相同疾病的散发病例的数据集提供了该基因负责的验证 疾病。然后可以通过机制研究来研究疾病的发病机制。这种方法导致 我们在解析遗传性神经系统疾病方面保持一致的生产力记录。 对于功能研究，我们重点关注 RAB39B α-突触核蛋白病、ATP6AP2 tau 蛋白病和 SAMD9L 共济失调、全血细胞减少症和自身免疫综合征，我们发现了三种疾病的致病基因，以及 GBA，这是已知最强的特发性帕金森病遗传风险因素。这四个基因参与 内溶酶体运输和自噬，这些途径经常涉及帕金森病和其他神经退行性疾病 失调。通过分析人体尸检大脑样本中的基因表达，我们将识别脆弱的细胞 类型并表征驱动病理学的区域特定变化。神经细胞和神经胶质细胞重新编程 患者的诱导多能干细胞（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 功能缺陷之间的联系，都会受到损害 自噬和易于聚集的 tau 蛋白的周转。自噬将通过药理学诱导 探索缓解 tau 病理学并提高神经元存活率。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 中的致病变异如何， ATP6AP2 和 SAMD9L 影响内溶酶体运输。 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 有助于我们理解神经变性中涉及的复杂蛋白质-蛋白质相互作用。 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额外的信息 这些疾病的候选基因也可以被视为干预目标。