Identifying symptomatic and neuroprotective strategies for cerebellar ataxia

摘要 小脑共济失调，一组致残和无法治疗的神经退行性疾病，影响多达15万人 在美国的人，导致不协调的肢体和躯干运动和福尔斯，经常导致 坐轮椅在细胞水平上，共济失调主要与脑内的神经元丢失有关。 小脑及其相关通路。神经元功能障碍先于并伴随神经元损失， 导致运动症状，但对这些早期事件的机制知之甚少。 在脊髓小脑共济失调1型（SCA 1）中，研究得最好，也是最常见的一种， 遗传性共济失调，小脑浦肯野神经元细胞大小减少和树突分支先于明显的 神经元缺失，就像其他共济失调一样。基于我们之前的工作， 在不同的共济失调小鼠模型中，小脑神经元的损伤导致运动缺陷，我们现在试图 确定浦肯野神经元功能的变化是否有助于改变形态和运动 SCA 1中的功能障碍。浦肯野神经元产生自主的，起搏动作电位，即使在 缺乏突触输入。我们在SCA 1小鼠模型中的初步数据表明，浦肯野神经元 起搏器放电最初是正常的，但到5周龄时，起搏器放电被破坏， 膜电位异常去极化与阈下激活的 钾离子通道引人注目的是，随后的浦肯野细胞萎缩与相对恢复有关。 起搏器放电，表明细胞收缩可能反映了浦肯野神经元试图补偿 生理功能障碍我们推测阈下激活钾通道的异常活动 是SCA 1发病机制中的关键早期事件。我们还假设， 维持正常的浦肯野起搏器放电有助于细胞收缩-这实际上是有益的-但是， 这种补偿的失败导致神经变性。在以下具体目标中，我们建议测试这些 在细胞和电路水平的假设，并探讨是否预防钾通道功能障碍， 改善神经变性和运动功能障碍。 该项目有三个目标。目的1将确定SCA 1中膜去极化的机制 浦肯野神经元。目标2将确定浦肯野神经元萎缩对小脑回路的影响， 目标3将确定维持正常的膜电位是否会防止浦肯野神经元萎缩 并改善SCA 1转基因小鼠的运动症状。

Abstract Cerebellar ataxias, a group of disabling and untreatable neurodegenerative disorders affecting up to 150,000 people in the United States, result in uncoordinated limb and trunk movements and falls, frequently leading to wheelchair confinement. At the cellular level, the ataxias are primarily associated with neuronal loss within the cerebellum and its associated pathways. Neuronal dysfunction precedes and accompanies neuronal loss and contributes to motor symptoms, but the mechanisms responsible for these early events are poorly understood. In Spinocerebellar Ataxia type 1 (SCA1), the best studied and one of the more common dominantly inherited ataxias, a reduction in cerebellar Purkinje neuron cell size and dendritic arborization precedes overt neuronal loss, as in other ataxias. Building on our prior work establishing that electrophysiological dysfunction of cerebellar neurons contributes to motor deficits in different mouse models of ataxia, we now seek to determine whether changes in Purkinje neuron function contribute to altered morphology and motor dysfunction in SCA1. Purkinje neurons generate autonomous, pacemaker action potentials even in the absence of synaptic input. Our preliminary data in a mouse model of SCA1 demonstrate that Purkinje neuron pacemaker firing is initially normal, but by 5 weeks of age, pacemaker firing is disrupted, together with abnormal depolarization of membrane potential associated with reduced activity of subthreshold-activated potassium channels. Strikingly, subsequent Purkinje cell shrinkage is associated with relative restoration of pacemaker firing, indicating that cell shrinkage may reflect the attempt of Purkinje neurons to compensate for physiologic dysfunction. We hypothesize that abnormal activity of subthreshold-activated potassium channels is a critical early event in the pathogenesis of SCA1. We also hypothesize that compensatory mechanisms to maintain normal Purkinje pacemaker firing contribute to cell shrinkage - which is actually beneficial - but that failure of this compensation leads to neurodegeneration. In the following specific aims we propose to test these hypotheses at the cell and circuit level, and to explore whether preventing potassium channel dysfunction will ameliorate neurodegeneration and motor dysfunction. The project has three aims. Aim 1 will determine the mechanism underlying membrane depolarization in SCA1 Purkinje neurons. Aim 2 will determine the consequences of Purkinje neuron atrophy on cerebellar circuitry, and aim 3 will determine whether maintaining normal membrane potential will prevent Purkinje neuron atrophy and improve motor symptoms in SCA1 transgenic mice.