Identifying symptomatic and neuroprotective strategies for cerebellar ataxia

描述（由申请人提供）：小脑共济失调是一组致残和无法治疗的神经退行性疾病，在美国影响多达150,000人，导致肢体和躯干运动不协调和跌倒，经常导致轮椅限制。在细胞水平上，共济失调主要与小脑及其相关通路内的神经元丢失有关。神经元功能障碍先于并伴随神经元丧失，并导致运动症状，但这些早期事件的机制尚不清楚。在脊髓小脑性共济失调1型（SCA1）中，研究得最好，也是最常见的显性遗传性共济失调之一，与其他共济失调一样，小脑浦肯野神经元细胞大小和树突状树突的减少先于明显的神经元损失。在我们之前的工作基础上，我们建立了小脑神经元的电生理功能障碍有助于不同的共济失调小鼠模型的运动缺陷，我们现在试图确定浦肯野神经元功能的改变是否有助于SCA1的形态改变和运动功能障碍。即使在没有突触输入的情况下，浦肯野神经元也能产生自主的起搏器动作电位。我们在SCA1小鼠模型中的初步数据表明，浦肯野神经元起搏器的放电最初是正常的，但到5周龄时，起搏器的放电被破坏，同时伴有与阈下激活钾通道活性降低相关的膜电位异常去极化。引人注目的是，随后的浦肯野细胞萎缩与起搏器放电的相对恢复有关，这表明细胞萎缩可能反映了浦肯野神经元对生理功能障碍的补偿。我们假设阈下活化钾通道的异常活动是SCA1发病机制的关键早期事件。我们还假设维持正常浦肯野起搏器放电的代偿机制有助于细胞收缩——这实际上是有益的——但这种代偿机制的失败导致神经退行性变。在接下来的具体目标中，我们建议在细胞和回路水平上验证这些假设，并探讨预防钾通道功能障碍是否会改善神经退行性变性和运动功能障碍。该项目有三个目标。目的1将确定SCA1浦肯野神经元膜去极化的机制。目的2将确定浦肯野神经元萎缩对小脑回路的影响，目的3将确定维持正常的膜电位是否会预防浦肯野神经元萎缩并改善SCA1转基因小鼠的运动症状。

DESCRIPTION (provided by applicant): 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.