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

基本信息

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
项目类别：
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&apos 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

项目摘要

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（由应用程序提供）：我们的实验室发现，在三个报告的受影响家庭中，spinocerebellar共济失调（SCA5）导致spinocerebellar共济失调。在德国家族中发现的第三个突变，位于-III谱的ARP1结合区域中，如果功能性，则可能引起动力蛋白 - 二奈氏蛋白介导的蛋白质转运的全身功能障碍。和亨廷顿疾病，SCA1（脊椎动物共济失调1）和ALS（amootrophic侧向造成术）。为了评估SCA5突变是否会影响蔬菜介导的蛋白质转运并引起神经退行性，我们已经生成并开始表征SCA5的苍蝇模型。使用GAL4 -UAS表达系统，在神经元，卵巢和不同的蝇组织中表达人�-III谱或携带SCA5突变。我们的实验策略还旨在揭示可能在共济失调中机械相关的其他功能。为了更深入地了解谱蛋白在共济失调中的作用和SCA5突变的分子后果，我们正在筛选共济失调患者的DNA库中SPTBN2的其他突变以及Spectrin beta-non beta-non eryythrocyte 5 Gene（SPTBN5）中的突变（SPTBN5）。这项研究可以导致发现某些类型的共济失调的病因和机制的发现和更好地理解，这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直接和明确的疾病诊断提供工具。此外，对生化水平上疾病的原因的理解将是在未来治疗的药物或其他疗法的设计中有价值的投入。