Role of spectin mutations in Spinocerebellar Ataxias

描述（由申请人提供）：我们的实验室发现，在三个报告的受影响家庭中，¿-III谱蛋白（SPTBN2）突变导致脊髓小脑性共济失调5型（SCA5）。美国和法国的SCA5家族在第三个光谱重复序列中分别有39和15 bp的帧内缺失。这些变化很可能破坏四聚体α - β谱蛋白复合物的组织。在一个德国家族中发现的第三个突变位于¿-III谱蛋白的ARP1结合区，如果起作用，可能导致动力蛋白-动力蛋白介导的蛋白质运输的全身性功能障碍。Spectrin突变是共济失调的新原因，共济失调是一种神经退行性疾病，可能影响谷氨酸信号传导，以及囊泡运输，这是先前与阿尔茨海默病和亨廷顿病、脊髓小脑共济失调1 （SCA1）和肌萎缩性侧索硬化（ALS）有关的途径。此外，有大量报道称，在其他物种中，¿-III谱蛋白同源物的突变导致了运动障碍。为了评估SCA5突变是否会影响囊泡介导的蛋白质转运并导致神经退行性变，我们已经建立并开始表征SCA5的Fly模型。人类¿-III spectrin无论是野生型还是携带SCA5突变，都是通过GAL4-UAS表达系统在神经元、卵巢和不同的苍蝇组织中表达的。我们的实验策略还旨在揭示可能与共济失调机制相关的-幽灵蛋白的其他功能。为了更深入地了解谱蛋白在共济失调中的作用以及SCA5突变的分子后果，我们正在筛选共济失调患者的DNA库，以寻找SPTBN2和谱蛋白β -非红细胞5基因（SPTBN5）的额外突变。这项研究可以发现并更好地理解某些类型的共济失调的病因和发病机制，共济失调是一组影响人类神经系统的遗传疾病。发现共济失调的原因将为这种疾病的直接和明确的诊断提供工具。此外，在生化水平上了解该疾病的原因将是未来设计药物或其他治疗方法的宝贵投入。

DESCRIPTION (provided by applicant): Our lab has discovered that ¿-III spectrin (SPTBN2] mutations cause spinocerebellar ataxia type 5 (SCA5), in three reported affected families. The American and the French SCA5 families have separate in-frame deletions of 39 and 15 bp, respectively, in the third spectrin repeat. These changes are likely to disrupt the organization of the tetrameric alpha-beta spectrin complex. A third mutation, found in a German family, is located in the ARP1 binding region of ¿-III spectrin, which, if functional, could cause generalized dysfunction of dynein-dynactin mediated protein transport. Spectrin mutations are a novel cause of ataxia, a neurodegenerative disease that may affect glutamate signaling, as well as vesicle trafficking, pathways previously implicated in Alzheimer and Huntington diseases, SCA1 (Spinocerebellar Ataxia 1) and ALS (Amyotrophic Lateral Schlerosis). Furthermore, there are extensive reports of mutations in ¿-III spectrin homologues causing movement disorders in other species. To assess whether the SCA5 mutations can affect vesicle-mediated protein transport and cause neurodegeneration, we have generated and begun to characterize a Fly model of SCA5. Human ¿-III spectrin either wild type or carrying the SCA5 mutations is being expressed in neurons, ovaries and different fly tissues using the GAL4-UAS expression system. Our experimental strategy is also designed to uncover other functions of ¿-spectrins that might turn out to be mechanistically relevant in ataxia. To gain a deeper understanding of the role of spectrin proteins in ataxia and the molecular consequences of the SCA5 mutations, we are screening a DNA bank of ataxia patients for additional mutations in SPTBN2 as well as mutations in the spectrin beta-non erythrocyte 5 gene (SPTBN5). This research can result in the discovery and better understanding of the causes and mechanisms of pathogenesis of some types of ataxia, a group of genetic diseases that affect the nervous systems in humans. The discovery of the causes of ataxia would offer tools for the direct and unambiguous diagnosis of the disease. Additionally, an understanding of the causes of the disease at the biochemical level would be valuable input in the design of drugs or other therapies for its treatment in the future.