Identifying symptomatic and neuroprotective strategies for cereballar ataxia

确定小脑共济失调的症状和神经保护策略

基本信息

批准号：
10394772
负责人：
Vikram Govindaraju Shakkottai
金额：
$ 50.68万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-20 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10394772
关键词：
Address Ataxia Bacterial Artificial Chromosomes Biology Brain Brain Stem Cause of Death Cell physiology Cerebellar Ataxia Cerebellum Cessation of life Data Disease Electrophysiology (science)Event Functional disorder Funding Genes Genetic Transcription Genetic study Glutamine Immunoprecipitation Impairment Inferior Ion Channel Knock-in Knock-in Mouse LY6E gene Lead Link MJD1 protein Mediating Membrane Modeling Molecular Motor Nerve Degeneration Neuronal Dysfunction Neurons Olives - dietary Pathogenesis Pathogenicity Pathway interactions Physiology Play Potassium Potassium Channel Proteins Publications Purkinje Cells RNA RNA Stability Role Series Slice Spinocerebellar Ataxias Transcript Transgenic Mice Transgenic Model Transgenic Organisms Viral Work chromatin immunoprecipitation improved in vivo insight motor disorder mouse genetics mouse model mutant neuron loss polyglutamine premature targeted treatment therapeutic target transcriptomics

项目摘要

A remarkable feature of the neurodegenerative spinocerebellar ataxias (SCAs) is that glutamine encoding CAG (polyQ) expansions in a diverse set of genes all cause Purkinje cell (PC) and brainstem neuron degeneration. This fact suggests that these genetically distinct polyQ SCAs share key upstream pathogenic events. While PC dysfunction may principally drive motor dysfunction in polyQ SCAs, brainstem dysfunction more closely correlates with premature death. This proposal explores unifying molecular events causing neuronal dysfunction and degeneration in ataxia, with a focus on the polyQ SCAs. In a series of recent publications supported by new data, we identified alterations in potassium (K+) channels as a key feature in several polyQ SCAs. Importantly, in SCA1 transgenic mice, we previously showed that restoring K+ channel expression or function rescued membrane hyperexcitability, improved motor dysfunction and reduced PC degeneration. It is now important to examine the links between K+ channel dysregulation and altered membrane excitability in cerebellar and brainstem neurons, and the relationship of these events to motor dysfunction and neurodegeneration in several polyQ SCAs. In the prior funding period we identified K+ channel dysfunction as the basis of PC spiking abnormalities in models of the polyQ ataxias SCA1, SCA2, SCA3 and SCA7, which together account for the majority of SCAs. To explore shared links between neuronal dysfunction and these functionally diverse polyQ disease proteins, we applied unbiased transcriptomics in models of SCA1, SCA2 and SCA7, and identified a common theme, beginning early in disease: significant reduction in cerebellar transcripts for key ion channels important for K+ channel function. Preliminary data also suggest a reduction in K+ channel transcripts in SCA1 medullary brainstem neurons. The proposal seeks to determine whether altered K+ channel function tied to the biology of diverse polyQ proteins in regulating the transcription and/or stability of ion channel transcripts is a unifying mechanism underlying neuronal dysfunction and degeneration in polyQ SCAs through the following aims: Aim 1: Determine whether there is shared potassium channel dysfunction in cerebellar Purkinje cells and brainstem neurons in SCA1. Aim 2: Determine whether shared Purkinje cell dysfunction is responsible for motor dysfunction and neurodegeneration in SCA1, SCA2 and SCA7. Aim 3: Define the basis for shared reduction in ion channel transcripts in SCA1, SCA2 and SCA7. We anticipate that successful completion of these studies will definitively establish the important role of K+ channel dysfunction in the disease pathogenesis of a wide variety of polyQ ataxias. Further, these studies will demonstrate that abnormal Purkinje neuron spiking causes motor dysfunction in SCAs Lastly, the proposed work will also answer whether K+ channels are compelling therapeutic targets to counter cerebellar and brainstem dysfunction in cerebellar ataxia.

神经退行性脊髓小脑共济失调 (SCA) 的一个显着特征是谷氨酰胺编码 CAG (polyQ) 的多种基因扩展都会导致浦肯野细胞 (PC) 和脑干神经元退化。这一事实表明，这些遗传上不同的 PolyQ SCA 共享关键的上游致病基因。事件。虽然 PC 功能障碍可能主要导致 PolyQ SCA 中的运动功能障碍，但脑干功能障碍与过早死亡的关系更为密切。该提案探讨了统一分子事件导致共济失调中的神经元功能障碍和变性，重点关注 PolyQ SCA。在最近一系列由新数据支持的出版物中，我们发现了钾 (K+) 的变化通道是多个 PolyQ SCA 中的一个关键功能。重要的是，在 SCA1 转基因小鼠中，我们之前表明恢复 K+ 通道表达或功能可挽救膜过度兴奋性，改善运动能力功能障碍并减少 PC 退化。现在重要的是检查 K+ 通道之间的联系小脑和脑干神经元的失调和膜兴奋性改变，以及这些事件导致了几种 PolyQ SCA 的运动功能障碍和神经退行性变。在之前的资助期间，我们确定 K+ 通道功能障碍是 PC 尖峰异常的基础在 PolyQ 共济失调 SCA1、SCA2、SCA3 和 SCA7 模型中，它们共同占了大部分 SCA。探索神经元功能障碍与这些功能多样的 PolyQ 疾病之间的共同联系蛋白质，我们在 SCA1、SCA2 和 SCA7 模型中应用无偏转录组学，并确定了一个共同的主题，从疾病早期开始：关键离子通道的小脑转录本显着减少，很重要用于K+通道功能。初步数据还表明 SCA1 髓质中 K+ 通道转录本减少脑干神经元。该提案旨在确定 K+ 通道功能的改变是否与生物学相关调节离子通道转录本的转录和/或稳定性的不同的polyQ蛋白是一个统一的 PolyQ SCA 中神经元功能障碍和退化的机制通过以下目标实现： 1：确定小脑浦肯野细胞和脑干是否存在共同的钾通道功能障碍 SCA1 中的神经元。目标 2：确定共同的浦肯野细胞功能障碍是否与运动有关 SCA1、SCA2 和 SCA7 的功能障碍和神经变性。目标 3：确定共享减排的基础 SCA1、SCA2 和 SCA7 中的离子通道转录本。我们预计这些研究的成功完成将明确确定 K+ 通道功能障碍在多种疾病发病机制中的重要作用各种polyQ共济失调。此外，这些研究将证明异常的浦肯野神经元尖峰会导致 SCA 中的运动功能障碍最后，拟议的工作还将回答 K+ 通道是否引人注目治疗目标是对抗小脑性共济失调中的小脑和脑干功能障碍。