Role of spectin mutations in Spinocerebellar Ataxias

描述(由申请人提供)：我们的实验室在三个报告的受影响家庭中发现？-III血影蛋白(SPTBN2)突变导致脊髓小脑性共济失调5型(SCA5)。在第三个血影蛋白重复序列中，美国人和法国人的SCA5家族分别有39和15个碱基对的框内缺失。这些变化可能会扰乱四聚体α-β血影蛋白复合体的组织。第三个突变是在一个德国家庭中发现的，位于血影蛋白的ARP1结合区，如果具有功能，可能会导致动力蛋白-动力蛋白介导的蛋白质运输的全身性功能障碍。血影蛋白突变是导致共济失调的新原因，共济失调是一种神经退行性疾病，可能影响谷氨酸信号转导和囊泡运输，这些途径以前与阿尔茨海默病和亨廷顿病、脊髓小脑性共济失调1和肌萎缩侧索硬化症有关。此外，有大量的报告表明，在其他物种中，血影蛋白同源物的突变会导致运动障碍。为了评估SCA5突变是否可以影响囊泡介导的蛋白质运输并导致神经退化，我们已经建立并开始表征SCA5的苍蝇模型。利用GAL4-UAS表达系统，野生型或携带SCA5突变的人-III幽灵蛋白在神经元、卵巢和不同的苍蝇组织中表达。我们的实验策略也是为了揭示幽灵蛋白的其他功能，这些功能可能会在共济失调中被证明是机械相关的。为了更深入地了解血影蛋白在共济失调中的作用和SCA5突变的分子后果，我们正在筛选共济失调患者的DNA文库，以寻找SPTBN2的额外突变以及血影蛋白β非红细胞5基因(SPTBN5)的突变。这项研究可以发现和更好地了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性疾病。共济失调病因的发现将为疾病的直接和明确诊断提供工具。此外，在生化水平上了解该病的病因，将是今后设计治疗该病的药物或其他疗法的宝贵投入。

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.