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

项目总结/摘要 脊髓小脑性共济失调1型（SCA 1）是一种破坏性的神经退行性疾病，其特征在于进行性 小脑变性引起的共济失调死亡通常发生在生命的第三至第六个十年。而 SCA 1的标志是运动协调或共济失调的丧失，在疾病的终末期导致过早死亡 继发于延髓功能障碍的并发症，包括吞咽困难和呼吸功能障碍。 在SCA 1中，疾病是由ATAXIN 1中编码多聚谷氨酰胺（polyQ）的CAG重复序列扩增引起的 （Atxn 1）。大量的努力已经投入到确定导致小脑的分子机制， 变性，特别是浦肯野细胞死亡，从polyQ扩展Atxn 1。这主要是因为， 浦肯野细胞似乎是SCA 1中最先受到影响的神经元，它们最容易受到致病性神经元的攻击。 扩大polyQ Atxn 1的后遗症。然而，浦肯野细胞的损失并不能解释球功能障碍 表型，最终导致过早死亡。我假设运动神经元退化 在SCA 1中负责延髓功能障碍。SCA 1尸检数据进一步支持了这一假设， 脑干中运动神经元的明显丧失。在2002年，我们的实验室开发了SCA 1的关键小鼠模型 概括了疾病的主要人类特征，具有鲁棒的面孔和结构效度。在这个模型中， 命名为Atxn 1 - 154 Q，将154个CAG重复敲入内源小鼠Atxn 1基因座。后 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，我做出了令人兴奋的观察， 这些小鼠表现出明显的运动神经元退化的迹象。特别是我注意到明显的肌肉 24周龄时出现消瘦、呼吸异常和痉挛。本提案的目的是审查 Atxn 1 - 154 Q小鼠运动神经元的功能、形态和分子水平，以便更好地了解 是什么导致了它们的退化，并建立这些小鼠作为研究运动神经元的理想模型， SCA 1中的退化。

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.