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不可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福尔斯，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损失相关。神经元功能障碍先于并伴随神经元损失，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（SCA 1）是研究最多的显性遗传性共济失调之一，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丢失，与其他共济失调一样。建立在我们以前的工作，建立小脑神经元的电生理功能障碍，有助于运动障碍，在不同的小鼠模型的共济失调，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功能障碍的SCA 1。浦肯野神经元即使在没有突触输入的情况下也能产生自主的起搏动作电位。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，以及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补偿生理功能障碍的尝试。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-但这种补偿的失败导致神经退行性变。在下面的具体目标中，我们建议在细胞和回路水平上测试这些假设，并探索预防钾通道功能障碍是否会改善神经退行性疾病和运动功能障碍。该项目有三个目标。目的1将确定SCA 1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后果，目的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。

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.