Investigating the Pathogenesis of Cerebellar Neurodegeneration

描述(申请人提供)：遗传性共济失调是一组遗传性疾病，具有相同的神经和病理特征，如平衡和协调能力丧失，以及小脑神经变性。我的实验室的最终研究目标是了解导致小脑退行性疾病的细胞和分子机制，以便开发有效的治疗措施来治疗这类神经退行性疾病。为了开始识别这些机制，我们之前为23种不同的遗传性共济失调相关的蛋白质生成了一个蛋白质-蛋白质相互作用网络。这项研究和其他几项研究表明，Wnt-β-catenin信号通路可能在遗传性共济失调的一部分(如果不是全部)中普遍受到影响。然而，在遗传性共济失调的小脑中，Wnt-连环蛋白信号通路是否真的受到影响，或者Wnt-连环蛋白信号通路的活性改变是否与小脑神经退行性变有关，目前尚不清楚。为了解决这些问题，我们使用脊髓小脑性共济失调1型(SCA1)作为遗传性小脑性共济失调的原型。SCA1是一种遗传性神经退行性疾病，以小脑浦肯野细胞(PC)、脑干脑神经核团、下橄榄核团和脊髓小脑束进行性变性为特征。SCA1是由ATAXIN1(ATXN1)中的谷氨酰胺扩张引起的。本申请中提供的初步数据清楚地表明，Wnt-？-catenin信号通路在正常小鼠小脑的正常PC中是功能活跃的，并且这种激活是 在SCA1小鼠的PC中显著增强。我们还提供了证据表明，在SCA1受影响的神经元，如小脑PC和下橄榄，Wnt-β-catenin信号的增强激活导致成人小脑PC萎缩和/或退化。这些数据有力地支持了Wnt-连环蛋白信号可能在成人小脑生理和/或小脑神经退行性变中起关键作用的观点。在这里，我们假设致病突变ATXN1蛋白在SCA1小鼠中强烈激活Wnt-？-catenin信号，超出正常水平，并且这种上调足以导致PC功能障碍和退化。为了研究这一假说，我们将进行以下具体研究：1)探索Wnt-连环蛋白信号在正常成人小脑PC功能/存活中的作用；2)确定多谷氨酰胺扩展突变体ATXN1激活Wnt-连环蛋白信号的分子机制；3)确定Wnt-连环蛋白信号增强激活在SCA1发病机制中的体内相关性。从这项应用中提出的研究中获得的知识将促进我们对小脑神经变性潜在的细胞和分子机制的理解，并将提出旨在减轻这些毁灭性疾病负担的新的治疗干预措施。

DESCRIPTION (provided by applicant): The hereditary ataxias are a group of genetic disorders that share neurological and pathological features, such as loss of balance and coordination, as well as cerebellar neurodegeneration. The ultimate research goal of my laboratory is to understand the cellular and molecular mechanisms that are responsible for cerebellar degeneration in order to develop effective therapeutic interventions for this class of neurodegenerative diseases. To begin to identify these mechanisms, we previously generated a protein-protein interaction network for proteins associated with twenty-three different inherited ataxias. This study and several others suggest that the Wnt-¿-catenin signaling pathway may be commonly affected in a subset, if not all, of the hereditary ataxias. However, it has not been determined yet whether Wnt-¿-catenin signaling is indeed affected in cerebellum in vivo in the hereditary ataxias or whether the altered activity of the Wnt-¿-catenin signaling pathway is responsible for the cerebellar neurodegeneration. To address these questions, we use spinocerebellar ataxia type 1 (SCA1) as a prototype of hereditary cerebellar ataxias. SCA1 is a dominantly inherited neurodegenerative disorder characterized by progressive degeneration of cerebellar Purkinje cells (PCs), brainstem cranial nerve nuclei and inferior olive nuclei, and spinocerebellar tracts. SCA1 is caused by a glutamine expansion in ATAXIN1 (ATXN1). The preliminary data presented in this application clearly show that the Wnt-¿-catenin signaling pathway is functionally active in normal PCs in the adult cerebellum in mice and this activation is strongly enhanced in PCs in SCA1 mice. We also provide evidence that the enhanced activation of Wnt-¿-catenin signaling in SCA1-affected neurons, such as cerebellar PCs and the inferior olive, results in cerebellar PC atrophy and/or degeneration in adults. These data strongly support the idea that Wnt- ¿-catenin signaling may have a crucial role in the physiology of the adult cerebellum and/or in cerebellar neurodegeneration. Here, we hypothesize that the disease-causing mutant ATXN1 protein strongly activates Wnt-¿-catenin signaling beyond the normal level in SCA1 mice, and that this upregulation is sufficient to cause PC dysfunction and degeneration. To investigate this hypothesis we will perform the following specific studies: 1) Explore the role of Wnt-¿-catenin signaling in PC function/survival in the normal adult cerebellum; 2) Identify the molecular mechanisms by which polyglutamine-expanded mutant ATXN1 activates Wnt-¿-catenin signaling; 3) Determine the in vivo relevance of enhanced activation of Wnt-¿-catenin signaling in SCA1 pathogenesis. The knowledge gained from the studies proposed in this application will advance our understanding of the cellular and molecular mechanisms underlying cerebellar neurodegeneration and will suggest new therapeutic interventions aimed at reducing the burden of these devastating diseases.