Identifying symptomatic and neuroprotective strategies for cerebellar ataxia

描述（由申请人提供）：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 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内的神经元损失及其相关通路有关。神经元功能障碍先于神经元损失并伴随神经元损失，并导致运动症状，但对这些早期事件的机制知之甚少。 脊髓小脑性共济失调 1 型 (SCA1) 是研究最深入、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枝化的减少先于明显的神经元损失。基于我们之前的工作，确定小脑神经元的电生理功能障碍会导致不同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变化是否会导致 SCA1 形态的改变和运动功能障碍。即使在没有突触输入的情况下，浦肯野神经元也会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放电最初是正常的，但到 5 周龄时，起搏器放电被破坏，同时膜电位异常去极化与阈下激活的钾通道活性降低相关。引人注目的是，随后的浦肯野细胞收缩与起搏器放电的相对恢复相关，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。我们假设阈下激活钾通道的异常活性是 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补偿机制有助于细胞收缩——这实际上是有益的——但这种补偿的失败会导致神经退行性变。在以下具体目标中，我们建议在细胞和回路水平上测试这些假设，并探讨预防钾通道功能障碍是否会改善神经退行性和运动功能障碍。该项目有三个目标。目标 1 将确定 SCA1 浦肯野神经元膜去极化的机制。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.