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，具有共同的神经和病理特征，例如平衡和协调能力丧失以及小脑神经退行性变。我实验室的最终研究目标是了解小脑变性的细胞和分子机制，以便为这类神经退行性疾病开发有效的治疗干预措施。为了开始识别这些机制，我们先前为与23种不同遗传性共济失调相关的蛋白质生成了蛋白质-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信号通路可能在一个子集（如果不是全部）遗传性共济失调中受到普遍影响。然而，尚未确定Wnt-β-catenin信号通路是否确实在遗传性共济失调中的小脑中受到体内影响，或者Wnt-β-catenin信号通路的活性改变是否是小脑神经变性的原因。为了解决这些问题，我们使用脊髓小脑共济失调1型（SCA 1）作为遗传性小脑共济失调的原型。SCA 1是一种显性遗传的神经退行性疾病，其特征在于小脑浦肯野细胞（PC）、脑干颅神经核和下橄榄核以及脊髓小脑束的进行性变性。SCA 1是由ATAXIN 1（ATXN 1）中的谷氨酰胺扩增引起的。本申请中提供的初步数据清楚地表明，Wnt-β-连环蛋白信号通路在成年小鼠小脑中的正常PC中具有功能活性，并且这种激活是通过激活Wnt-β-连环蛋白信号通路来实现的。 在SCA 1小鼠的PC中强烈增强。我们还提供了证据表明，在SCA 1影响的神经元，如小脑PC和下橄榄，Wnt-β-连环蛋白信号的增强激活，导致小脑PC萎缩和/或变性的成年人。这些数据有力地支持了Wnt-β-catenin信号传导可能在成人小脑的生理学和/或小脑神经变性中起关键作用的观点。在这里，我们假设致病突变体ATXN 1蛋白强烈激活SCA 1小鼠中超出正常水平的Wnt-β-catenin信号传导，并且这种上调足以导致PC功能障碍和变性。为了研究这一假设，我们将进行以下具体研究：1）探索Wnt-β-catenin信号传导在正常成人小脑PC功能/存活中的作用; 2）确定多聚谷氨酰胺扩增突变体ATXN 1激活Wnt-β-catenin信号传导的分子机制; 3）确定Wnt-β-catenin信号传导增强激活在SCA 1发病机制中的体内相关性。从本申请中提出的研究中获得的知识将促进我们对小脑神经退行性变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.