Identifying symptomatic and neuroprotective strategies for cerebellar ataxia

描述(申请人提供)：小脑性共济失调是一组致残且无法治疗的神经退行性疾病，在美国影响多达15万人，导致肢体和躯干运动不协调并摔倒，经常导致轮椅禁闭。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。神经元功能障碍是神经元丢失的先兆和随之而来，并导致运动症状，但这些早期事件的机制尚不清楚。脊髓小脑型共济失调1型(SCA1)是研究最充分的，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，小脑浦肯野神经元体积缩小和树突分枝先于明显的神经元丢失。在我们之前工作的基础上，我们确定了小脑神经元的电生理功能障碍导致了不同的共济失调小鼠模型的运动障碍，现在我们试图确定浦肯野神经元功能的变化是否有助于SCA1的形态改变和运动功能障碍。浦肯野神经元即使在没有突触输入的情况下也会产生自主的起搏器动作电位。我们在SCA1小鼠模型上的初步数据显示，浦肯野神经元起搏器放电最初是正常的，但到5周时，起搏器放电被扰乱，伴随着与阈值下激活的钾通道活性降低相关的膜电位异常去极化。值得注意的是，随后的浦肯野细胞萎缩与起搏器放电的相对恢复有关，表明细胞萎缩可能反映了浦肯野神经元试图补偿生理功能障碍。我们假设，阈值下激活的钾通道的异常活动是SCA1发病机制中的一个关键早期事件。我们还假设，维持正常浦肯野起搏器放电的代偿机制会导致细胞萎缩--这实际上是有益的--但这种补偿的失败会导致神经退化。在以下具体目标中，我们建议在细胞和电路水平上检验这些假说，并探索预防钾通道功能障碍是否会改善神经退行性变和运动功能障碍。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神经回路的影响，目的3将确定维持正常的膜电位是否能防止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.