Nonneuronal Mechanisms of Polyglutamine Neurodegeneration

脊髓小脑共济失调3型（SCA 3），也称为马查多-约瑟夫病，是至少九种 疾病中编码异常长的多聚谷氨酰胺束的CAG重复扩增引起的疾病 proteins.尽管对疾病的理解有了进步，但关于CAG扩张如何影响血管的发展仍有许多未知之处。 SCA 3疾病基因ATXN 3导致脑功能障碍和细胞死亡。我们最近发现， SCA 3小鼠疾病脑区域的少突胶质细胞脆弱性，并在早期和稳健的 在疾病发病机制中涉及少突胶质细胞的变化。我们的长期目标是了解 SCA 3和相关多聚谷氨酰胺疾病的致病机制， 对于这些致命的和目前无法治疗的疾病，可以开发有希望的分子和细胞靶点。 为了实现这一目标，调查小组将利用其多样化的研究专长和广泛的 包括原代细胞培养物、小鼠模型和人类疾病组织的模型系统。根据最近 在小鼠模型和人类疾病组织中的发现，我们将研究非神经元对 疾病的发病机制，重点是少突胶质细胞谱系。在目标1中，我们将确定 少突胶质细胞功能障碍在SCA 3疾病中有多普遍。在目标2中，我们将生成新的条件 SCA 3小鼠模型，以建立突变蛋白是否引起细胞自主性少突胶质细胞功能障碍和 定义少突胶质细胞功能障碍对疾病发病机制的贡献。在目标3中，我们将阐明 SCA 3疾病中少突胶质细胞功能障碍的分子机制。这些研究结果 将有助于指导SCA 3和相关多聚谷氨酰胺疾病的治疗开发。

Spinocerebellar Ataxia type 3 (SCA3), also known as Machado-Joseph disease, is one of at least nine diseases caused by CAG repeat expansions that encode abnormally long polyglutamine tracts in the disease proteins. Despite advances in disease understanding, much remains unknown about how the CAG expansion in the SCA3 disease gene, ATXN3, causes brain dysfunction and cell death. We recently discovered selective oligodendrocyte vulnerability across SCA3 mouse disease brain regions and identified early and robust changes that implicate oligodendrocytes in disease pathogenesis. Our long-term objective is to understand pathogenic mechanisms in SCA3 and related polyglutamine diseases so that therapies targeting the most promising molecular and cellular targets can be developed for these fatal and currently untreatable disorders. Toward that objective, the team of investigators will leverage their diverse research expertise and a wide range of model systems including primary cell cultures, mouse models, and human disease tissue. Building on recent discoveries in mouse models and human disease tissue, we will investigate nonneuronal contributions to disease pathogenesis, with an emphasis on cells of the oligodendroglial lineage. In Aim 1, we will determine how widespread oligodendrocyte dysfunction is in SCA3 disease. In Aim 2, we will generate novel conditional SCA3 mouse models to establish if the mutant protein elicits cell-autonomous oligodendrocyte dysfunction and define oligodendrocyte dysfunction contributions to disease pathogenesis. In Aim 3, we will elucidate the molecular mechanisms that underlie oligodendrocyte dysfunction in SCA3 disease. Results of these studies will help guide therapeutic development in SCA3 and related polyglutamine diseases.