Nonneuronal Mechanisms of Polyglutamine Neurodegeneration

脊髓小脑型共济失调3型(SCA3)，也被称为马查多-约瑟夫病，是至少九种疾病之一 由CAG引起的疾病重复扩张，在疾病中编码异常长的聚谷氨酰胺束。 蛋白质。尽管在疾病认识方面取得了进展，但关于CAG如何扩展仍有许多未知之处 在SCA3疾病基因中，ATXN3会导致大脑功能障碍和细胞死亡。我们最近发现了选择性 SCA3病小鼠脑区的少突胶质细胞易损性及其早期和健壮性 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 SCA3和相关聚谷氨酰胺病的致病机制使治疗针对性最强 有希望的分子和细胞靶点可以为这些致命的和目前无法治疗的疾病而开发。 为了实现这一目标，调查小组将利用他们多样化的研究专长和广泛的范围 模型系统包括原代细胞培养、小鼠模型和人类疾病组织。在最近的基础上 在小鼠模型和人类疾病组织中的发现，我们将调查非神经元对 疾病发病机制，重点是少突胶质细胞系的细胞。在目标1中，我们将确定 少突胶质细胞功能障碍在SCA3病中有多普遍。在目标2中，我们将生成新的条件 建立SCA3小鼠模型以确定突变蛋白是否引起细胞自主少突胶质细胞功能障碍和 明确少突胶质细胞功能障碍在疾病发病机制中的作用。在目标3中，我们将阐明 SCA3病少突胶质细胞功能障碍的分子机制。这些研究的结果 将有助于指导SCA3和相关的聚谷氨酰胺疾病的治疗发展。

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.