Kv3.3 K+ Channels and Neuronal Excitability in Spinocerebellar Ataxia Type 13

Kv3.3 K 通道和 13 型脊髓小脑共济失调的神经元兴奋性

• 批准号: 7537199
• 负责人: Diane M Papazian
• 金额: $ 33.69万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-15 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7537199
• 关键词: Action Potentials; Affect; Age of Onset; Aging; Alzheimer' s Disease; Animal Model; Ataxia; Behavioral Genetics; Brain; Cell Death; Cerebellar degeneration; Cerebellar malformation; Cerebellum; Cytoplasmic Granules; Development; Disease; Drug Delivery Systems; Electric Stimulation; Etiology; Fire - disasters; Frequencies; Genes; Goals; In Vitro; Lead; Light; Measures; Mental Retardation; Motor Neurons; Mutation; Neurodegenerative Disorders; Neurons; Optics; Play; Potassium Channel; Predisposition; Prevention; Property; Purkinje Cells; Research; Rest; Role; Spinal Cord; Spinocerebellar Ataxias; Structure; Testing; Time; Type 1 Spinocerebellar Ataxia; Type 2 Spinocerebellar Ataxia; Voltage-Gated Potassium Channel; Zebrafish; age related; granule cell; human disease; infancy; locomotor deficit; mutant; neurodegenerative phenotype; neuron development; neuron loss; neuronal excitability; neuronal survival; response

DESCRIPTION (provided by applicant): Spinocerebellar ataxia type 13 (SCA13) is a dominant human disease characterized by locomotor problems and substantial volume loss in the cerebellum. SCA13 is caused by mutations in the KCNC3 gene, which encodes the voltage-gated K+ channel, Kv3.3. Two allelic forms of SCA13 have been described. One form emerges in adulthood and is characterized by progressive ataxia and cerebellar degeneration. The other form is evident in infancy and is characterized by severe locomotor problems, mental retardation, and cerebellar malformation. Thus, mutations in Kv3.3 are associated with both developmental and neurodegenerative phenotypes. Due to their specialized gating properties, Kv3 channels confer on neurons the ability to fire action potentials at high frequencies. Kv3 channels also control spike duration and thereby regulate activity- dependent Ca2+ influx. The two allelic forms of SCA13 are caused by different KCNC3 mutations that alter channel activity in distinct ways. The long term goal of this research is to test the hypotheses that SCA13 mutations alter the excitability of cerebellar neurons and do so in different ways, and that these changes in excitability affect the age of onset and lead to the locomotor deficits and changes in cerebellar structure that characterize the disease. The Specific Aims of this proposal are to test the hypotheses that: 1) SCA13 mutations differentially alter the excitability of cerebellar neurons, 2) SCA13 mutations differentially alter cytoplasmic Ca2+ load in response to electrical stimulation and affect neuronal survival in Ca2+- and age- dependent cell death paradigms, and 3) the unique gating properties of Kv3 channels play a previously unsuspected role in neuronal development. These Specific Aims will be accomplished using cerebellar neurons in vitro and a vertebrate model organism, the zebrafish Danio rerio, for electrophysiological, optical, genetic, and behavioral analysis. SCA13 is rare, but analysis of SCA13 disease mechanisms may shed light on the etiology of common neurodegenerative diseases such as Alzheimer's. Given the fact that mutations in K+ and Ca2+ channel genes lead to progressive neuronal cell death in SCA13 and SCA6, it is reasonable to suggest that changes in channel function or expression contribute to susceptibility or etiology in common neurodegenerative diseases. If changes in excitability contribute to neuronal cell death, the possibilities for prevention and treatment of neurodegenerative diseases would be greatly expanded because drugs that target specific channels and modulate excitability exist and continue to be discovered.

描述（由申请人提供）：13型脊髓脑性共济失调（SCA13）是一种主要的人类疾病，其特征是运动问题和小脑的大量体积损失。 SCA13是由KCNC3基因突变引起的，该基因编码电压门控k+通道Kv3.3。已经描述了两种等位基因形式的SCA13。一种形式出现在成年期，其特征是进行性共济失调和小脑变性。另一种形式在婴儿期很明显，其特征是严重的运动问题，智力低下和小脑畸形。因此，Kv3.3中的突变与发育和神经退行性表型均相关。由于其专门的门控特性，KV3通道赋予神经元以高频发射动作电位的能力。 KV3通道还控制峰值持续时间，从而调节依赖性CA2+流入。 SCA13的两种等位基因形式是由不同的KCNC3突变引起的，这些突变以不同的方式改变了通道活性。这项研究的长期目标是检验SCA13突变改变小脑神经元的兴奋性的假设，并以不同的方式进行，并且这些变化的兴奋性会影响发病的年龄，并导致运动不足和导致疾病表征疾病的小脑结构的变化。该建议的具体目的是测试以下假设：1）SCA13突变差异改变了脑神经元的兴奋性，2）SCA13突变差异改变了细胞质Ca2+负载，响应电刺激对电刺激的响应，并影响CA2+ - 依赖性病毒死亡范围的神经元持续性的神经元的生存。在神经元发展中的作用。这些特定目标将在体外使用小脑神经元和脊椎动物模型生物，斑马鱼Danio Rerio来实现，用于电生理，光学，遗传和行为分析。 SCA13很少见，但是对SCA13疾病机制的分析可能会阐明常见神经退行性疾病（例如阿尔茨海默氏病）的病因。鉴于K+和Ca2+通道基因的突变导致SCA13和SCA6导致进行性神经元细胞死亡，因此合理地表明，通道功能或表达的变化有助于常见神经退行性疾病的易感性或病因。如果兴奋性的变化导致神经元细胞死亡，则将大大扩展神经退行性疾病的预防和治疗的可能性，因为靶向特定通道和调节兴奋性的药物存在并继续被发现。