Genetic Movement Disorders: Etiologies and Pathogeneses

本申请提出鉴定遗传性运动障碍的分子病因学并阐明其作用 作为改善诊断和发展靶向治疗的重要步骤 治疗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，舞蹈病或张力障碍，都是遗传性的， 异质的我们已经确定了多种运动障碍的潜在基因，其中一些是 并对它们的发病机制进行了初步研究。更多的贡献基因还有待于 发现了我们建议：1）继续确定和描述具有遗传学特征的个人和家庭 非归因性运动障碍; 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）研究运动障碍的致病机制。 使用患者组织、患者来源的干细胞模型和果蝇模型的变体。该提案建立 建立协同合作和多方面的临床，病理，基础科学， 研究者和合作者的翻译专业知识。它还利用了两个 大量的样本收集，确定，广泛的特点，并延长超过30年 （神经遗传学和PD储存库）。 我们的疾病基因鉴定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，以鉴定以下基因共享的连锁/IBD区域中的变体： 受影响的亲戚统计遗传学的进步和更密集标记组的使用使得有可能 在更小的家族中进行这样的研究，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性变异以供进一步研究的方法。一个变异体与疾病的共分离， 单个家庭和鉴定其他家庭中相同基因的突变，以及大型公开可用的 具有相同疾病的散发病例的数据集提供了该基因负责该疾病的验证。 疾病疾病的发病机制，然后可以通过机制研究。这种做法导致 我们在分析遗传性神经系统疾病方面的一致生产力的记录。 对于功能性研究，我们集中在RAB 39 B α-突触核蛋白病、ATP 6AP 2 tau蛋白病和SAMD 9L 共济失调、全血细胞减少和自身免疫综合征，我们发现了三种疾病的致病基因， GBA是已知的特发性PD最强的遗传风险因素。这四个基因参与了 内溶酶体运输和自噬，经常涉及PD和其他神经退行性疾病的途径 紊乱通过分析人类尸检脑组织样本中的基因表达，我们将确定脆弱细胞， 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 患者的诱导多能干细胞（iPSC）将用于研究致病性变异体在 这些基因中的每一个，例如ATP 6AP 2/V-ATP酶功能缺陷之间的联系， 自噬和易于聚集的tau蛋白的周转。自噬将被诱导， 探索tau病理学的缓解并改善神经元存活。果蝇和iPSC模型将用于 研究RAB 39 B和ATP 6AP 2蛋白如何与GBA相互作用以及RAB 39 B中致病性变体， 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外，每个新基因 有助于我们理解神经退行性变中复杂的蛋白质-蛋白质相互作用。 此外，从它们的生物化学途径和蛋白质复合物中，每个新基因都可以发现额外的 也可以被认为是干预目标的疾病的候选基因。

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.