Identifying symptomatic and neuroprotective strategies for cereballar ataxia

神经退行性脊髓小脑性共济失调的一个显著特征是谷氨酰胺 在一组不同的基因中编码CAG(PolyQ)的扩张都会导致浦肯野细胞(PC)和脑干神经元 退化。这一事实表明，这些遗传上截然不同的多聚Q SCA共享关键的上游致病基因 事件。虽然PC功能障碍可能是多发性SCA患者运动功能障碍的主要原因，但脑干功能障碍 与过早死亡有更密切的关系。这项提案探索了统一的分子事件导致 共济失调中的神经元功能障碍和变性，重点是多Q SCA。 在最近一系列有新数据支持的出版物中，我们发现了钾(K+)的变化 通道是几个PolyQ SCA中的一个关键功能。重要的是，在SCA1转基因小鼠中，我们之前展示了 恢复K+通道表达或功能可挽救膜的过度兴奋性，改善运动 功能障碍和减少PC退行性变。现在重要的是检查K+通道之间的链接 小脑和脑干神经元调节失调和膜兴奋性改变及其相互关系 这些事件与多个多Q SCA的运动功能障碍和神经退行性变有关。 在之前的资金支持期间，我们确定K+通道功能障碍是PC峰值异常的基础 在多Q共济失调模型中，SCA1、SCA2、SCA3和SCA7加起来占大多数 SCAS。探索神经元功能障碍和这些功能不同的多Q病之间的共同联系 蛋白质方面，我们在SCA1、SCA2和SCA7模型中应用了无偏转录组分，并发现了一个共同的 主题，从疾病早期开始：关键离子通道小脑转录显著减少 对于K+通道功能。初步数据还表明，SCA1延髓中K+通道转录本减少 脑干神经元。该提案试图确定改变的K+通道功能是否与高血压的生物学联系在一起 不同的PolyQ蛋白在调节离子通道转录本的转录和/或稳定性方面是统一的 多聚Q-SCA中神经元功能障碍和变性的机制 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。目的2：确定共同浦肯野细胞功能障碍是否与运动有关 SCA1、SCA2和SCA7的功能障碍和神经退行性变。目标3：确定共同减排的基础 SCA1、SCA2和SCA7的离子通道转录本。我们期待着成功完成这些研究 将明确K+通道功能障碍在本病发病机制中的重要作用 多发性共济失调的种类。此外，这些研究将证明异常的浦肯野神经元放电导致 SCA的运动功能障碍最后，拟议的工作还将回答K+通道是否令人信服 针对小脑性共济失调患者小脑和脑干功能障碍的治疗靶点。

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.