Unraveling the mechanisms of motor neuron degeneration if Spinocerebellar Ataxia, type 1

项目摘要/摘要 脊髓小脑性共济失调1型(SCA1)是一种以进行性为特征的破坏性神经退行性疾病。 小脑变性所致的共济失调。死亡通常发生在生命的第三到六十年。而当 SCA1的特点是运动协调能力的丧失或共济失调，在疾病的末期导致过早死亡。 从继发于球功能障碍的并发症，包括吞咽困难和呼吸功能障碍。 在SCA1中，疾病是由编码聚谷氨酰胺(PolyQ)的CAG重复序列在ATAXIN1中扩大引起的 (Atxn1)在确定导致小脑的分子机制方面投入了大量的努力。 从多聚Q扩增的Atxn1退化，特别是Purkinje细胞死亡。这在很大程度上是因为 浦肯野细胞似乎是SCA1中第一个受到影响的神经元，它们最容易受到 扩张多聚Q的后遗症Atxn1。然而，浦肯野细胞的丧失并不能解释球功能障碍。 表型，最终导致过早死亡。我假设运动神经元变性是 对SCA1中的延髓功能障碍负责。SCA1尸检数据进一步支持了这一假设 脑干运动神经元明显丧失。2002年，我们实验室为SCA1开发了一个关键的小鼠模型 以强健的面孔和结构效度概括疾病的主要人类特征。在这个模型中， 命名为Atxn1-154Q，将154个CAG重复序列敲入内源性小鼠Atxn1基因座。vt.在.的基础上 加入Zoghbi实验室，凭借我在神经肌肉疾病方面的临床专业知识，我进行了令人兴奋的观察 这些小鼠表现出运动神经元退化的明显迹象。我特别注意到了重要的肌肉 24周龄前出现消瘦、呼吸异常和痉挛。这项提案的目标是审查 为了更好地了解Atxn1-154Q小鼠运动神经元的功能、形态和分子水平 是什么导致了它们的退变，并建立了这些小鼠作为研究运动神经元的理想模型 SCA1的退行性变。

PROJECT SUMMARY/ABSTRACT Spinocerebellar ataxia type 1 (SCA1) is a devastating neurodegenerative disease characterized by progressive ataxia from cerebellar degeneration. Death typically occurs by the third to sixth decade of life. While the hallmark of SCA1 is loss of motor coordination or ataxia, at the end stage of disease premature death results from complications secondary to bulbar dysfunction, including swallowing difficulties and breathing dysfunction. In SCA1, disease is caused by expansion of CAG repeats encoding poly-glutamine (polyQ) in ATAXIN1 (Atxn1). Substantial effort has been invested in determining the molecular mechanism leading to cerebellar degeneration, specifically Purkinje cell death, from polyQ expanded Atxn1. This is largely due to the fact that Purkinje cells seem to be the first neurons affected in SCA1 and they are most vulnerable to the pathogenic sequelae of expanded polyQ Atxn1. However, loss of Purkinje cells does not account for the bulbar dysfunction phenotype, which ultimately causes premature death. I hypothesize that motor neuron degeneration is responsible for bulbar dysfunction in SCA1. Further supporting this hypothesis is SCA1 autopsy data showing marked loss of motor neurons in the brainstem. In 2002 our lab developed a pivotal mouse model for SCA1 recapitulating the major human features of disease with robust face and construct validity. In this model, designated Atxn1-154Q, 154 CAG repeats were knocked into the endogenous mouse Atxn1 gene locus. Upon joining the Zoghbi lab, with my clinical expertise in neuromuscular diseases, I made the exciting observation that these mice display overt signs of motor neuron degeneration. In particular I noted significant muscle wasting, breathing abnormalities and spasticity by 24 weeks of age. The goals of this proposal are to examine motor neurons in Atxn1-154Q mice functionally, morphologically and molecularly in order to better understand what causes their degeneration and to establish these mice as an ideal model to study motor neuron degeneration in SCA1.