Investigating the Pathogenesis of Cerebellar Neurodegeneration

描述（由申请人提供）：遗传性共济失调是一组具有神经学和病理学特征的遗传性疾病，如失去平衡和协调，以及小脑神经变性。我实验室的最终研究目标是了解导致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。为了开始确定这些机制，我们之前为与23种不同的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-¿-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，在遗传性共济失调中，体内小脑中Wnt-¿-catenin信号通路是否确实受到影响，以及Wnt-¿-catenin信号通路活性的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，我们使用脊髓小脑共济失调1型（SCA1）作为遗传性小脑共济失调的原型。SCA1是一种显性遗传的神经退行性疾病，其特征是小脑浦肯野细胞（PCs）、脑干脑神经核、下橄榄核和脊髓小脑束进行性变性。SCA1是由ATAXIN1 （ATXN1）中的谷氨酰胺扩增引起的。本应用程序提供的初步数据清楚地表明，Wnt-¿-catenin信号通路在小鼠成年小脑正常pc中具有功能活性，并且这种激活是

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.