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

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：脊髓小脑性共济失调 13 型（SCA13）是一种主要的人类疾病，其特征是运动问题和小脑容量显着减少。 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。 SCA13 的两种等位基因形式已被描述。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 的突变与发育和神经退行性表型相关。由于其特殊的门控特性，Kv3 通道赋予神经元以高频激发动作电位的能力。 Kv3 通道还控制尖峰持续时间，从而调节活动依赖性 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通道活性。这项研究的长期目标是检验以下假设：SCA13 突变以不同的方式改变小脑神经元的兴奋性，这些兴奋性的变化会影响发病年龄并导致运动缺陷和小脑结构的变化是疾病的特征。该提案的具体目标是测试以下假设：1) SCA13 突变会差异性地改变小脑神经元的兴奋性，2) SCA13 突变会差异性地改变响应电刺激的细胞质 Ca2+ 负荷，并影响 Ca2+- 和年龄依赖性的神经元存活细胞死亡范式，3) Kv3 通道独特的门控特性在神经元发育中发挥着以前未曾预料到的作用。这些具体目标将使用体外小脑神经元和脊椎动物模型生物斑马鱼斑马鱼进行电生理学、光学、遗传和行为分析来实现。 SCA13 很罕见，但对 SCA13 疾病机制的分析可能有助于揭示阿尔茨海默病等常见神经退行性疾病的病因。鉴于 K+ 和 Ca2+ 通道基因的突变导致 SCA13 和 SCA6 中的进行性神经元细胞死亡，因此有理由认为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学。如果兴奋性的变化导致神经细胞死亡，那么预防和治疗神经退行性疾病的可能性将大大扩大，因为针对特定通道和调节兴奋性的药物存在并不断被发现。