Role of spectin mutations in Spinocerebellar Ataxias

观察蛋白突变在脊髓小脑共济失调中的作用

• 批准号: 7489923
• 负责人: Damaris N Lorenzo
• 金额: $ 2.68万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-27 至 2009-08-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7489923
• 关键词: Affect; Alzheimer' s Disease; American; Ataxia; Autopsy; Binding; Binding Sites; Biochemical; Cerebellar Diseases; Childhood; Chromosomes, Human, Pair 11; Complex; DNA Library; Depth; Development; Diagnosis; Disease; Disruption; Drosophila genus; Drug Design; Dynein ATPase; Erythrocytes; Exhibits; Family; Functional disorder; Future; Gene Expression; Generations; Genes; Genetic; German population; Germany; Glutamates; Hereditary Disease; Homologous Gene; Human; Huntington Disease; Laboratories; Lateral; Maps; Mediating; Modeling; Molecular; Movement Disorders; Mutation; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurons; Other Therapy; Ovary; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Proteins; Purkinje Cells; Reporting; Research; Role; Screening procedure; Series; Shapes; Signal Transduction; Spectrin; Spinocerebellar Ataxia Type 5; Spinocerebellar Ataxias; Structure; System; Testing; Tissues; Transgenes; Transgenic Organisms; Transport Vesicles; Type 1 Spinocerebellar Ataxia; Vesicle; beta Spectrin; design; dominant pure Cerebellar ataxia; dynactin; fly; insight; mutant; novel; protein transport; research study; tool; trafficking

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.

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族中，<$-III血影蛋白（SPTBN 2）突变导致脊髓小脑共济失调5型（SCA 5）。美国和法国SCA 5家族在第三血影蛋白重复序列中分别有39和15 bp的单独框内缺失。这些变化可能会破坏四聚体α-β血影蛋白复合物的组织。第三个突变，发现在一个德国家庭，位于ARP 1结合区的<$-III血影蛋白，如果功能，可能会导致普遍功能障碍的动力蛋白-动力蛋白介导的蛋白质转运。Spectrin突变是共济失调的一种新原因，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，这些途径先前与阿尔茨海默病和亨廷顿病、SCA 1（脊髓小脑共济失调1）和ALS（肌萎缩性侧索硬化症）有关。此外，有大量的报告表明，<$-III血影蛋白同源物的突变会导致其他物种的运动障碍。为了评估SCA 5突变是否会影响囊泡介导的蛋白质转运并导致神经退行性变，我们已经生成并开始表征SCA 5的Fly模型。人类使用GAL 4-UAS表达系统，野生型或携带SCA 5突变的-III血影蛋白在神经元、卵巢和不同的蝇组织中表达。我们的实验策略还旨在揭示<$-spectroins的其他功能，这些功能可能与共济失调有关。为了更深入地了解血影蛋白在共济失调中的作用以及SCA 5突变的分子后果，我们正在筛选共济失调患者的DNA库中SPTBN 2的其他突变以及血影蛋白β-非红细胞5基因（SPTBN 5）的突变。这项研究可以导致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，这是一组影响人类神经系统的遗传疾病。共济失调病因的发现将为该疾病的直接和明确诊断提供工具。此外，在生物化学水平上了解疾病的原因将是设计药物或其他治疗方法的宝贵投入。