Dietary Contribution in Cerebellar Ataxia

项目摘要/摘要 小脑性共济失调是一种致残症状，可能有多种原因，其中 免疫介导的面筋共济失调是最常见的原因之一。面筋共济失调与 对转谷氨酰胺酶6(TG6)的自身免疫和一些面筋蛋白共济失调患者将 对无麸质饮食的反应。然而，无面筋饮食对面筋患者的反应 共济失调可能是可变的，目前尚不清楚TG6如何在共济失调中发挥作用 和/或对无面筋饮食的反应。最近，TGM6的基因突变，这种基因 编码TG6蛋白，已被鉴定为引起脊髓小脑性共济失调35型(SCA35)。 我们最近发现了一名SCA35患者，患者TGM6突变被截断，并患有小脑性共济失调， 无麸质饮食改善了他的共济失调，证明了遗传和免疫- 介导性原因可以汇聚在TG6生物学上，这是探索 饮食在神经性疾病中的作用。在这份R03提案中，我们将建立第一个 SCA35小鼠模型的建立及其对进行性共济失调(特异性)谷蛋白饮食的反应 目的1)、神经生理学(特异性目标2)和神经病理学(特异性目标3)。这只鼠标 模型将作为未来了解面筋生物学的机械学研究的基准 和小脑性共济失调。

PROJECT SUMMARY/ ABSTRACT Cerebellar ataxia is a disabling symptom and can have a variety of causes, among which immune-mediated gluten ataxia is one of the most common causes. Gluten ataxia is associated with autoimmunity against transglutaminase 6 (TG6) and some patients with gluten ataxia will respond to gluten-free diet. However, the responses to gluten-free diet in patients with gluten ataxia might be variable and there is no clear understanding how TG6 could play a role in ataxia and/or in response to gluten-free diet. Recently, genetic mutations of TGM6, the gene that encodes TG6 protein, have been identified to cause spinocerebellar ataxia type 35 (SCA35). We recently identified a SCA35 patient with a truncated TGM6 mutation and cerebellar ataxia, and his ataxia improved with gluten-free diet, demonstrating that both genetic and immune- mediated causes can converge at the TG6 biology, which serves as a window to probe the dietary contribution in neurological disorders. In this R03 proposal, we will establish the first mouse model of SCA35 and monitor its responses to gluten-diet in ataxia progression (Specific Aim 1), neurophysiology (Specific Aim 2), and neuropathology (Specific Aim 3). This mouse model will serve as a benchmark for future mechanistic studies to understand gluten biology and cerebellar ataxia.