Department of Genetics, Yale School of Medicine, 295 Congress Avenue, BCMM 154E, New Haven, CT, 06510, USA.
Interdepartmental Neuroscience Program, Yale School of Medicine, 295 Congress Avenue, BCMM 154E, New Haven, CT, 06510, USA.
Cell Mol Life Sci. 2022 Jul 8;79(8):404. doi: 10.1007/s00018-022-04419-7.
Spinocerebellar ataxia type 1 (SCA1) is one of nine polyglutamine (polyQ) diseases and is characterized as an adult late-onset, progressive, dominantly inherited genetic disease. SCA1 is caused by an increase in the number of CAG repeats in the ATXN1 gene leading to an expanded polyQ tract in the ATAXIN-1 protein. ATAXIN-1 is broadly expressed throughout the brain. However, until recently, SCA1 research has primarily centered on the cerebellum, given the characteristic cerebellar Purkinje cell loss observed in patients, as well as the progressive motor deficits, including gait and limb incoordination, that SCA1 patients present with. There are, however, also other symptoms such as respiratory problems, cognitive defects and memory impairment, anxiety, and depression observed in SCA1 patients and mouse models, which indicate that there are extra-cerebellar effects of SCA1 that cannot be explained solely through changes in the cerebellar region of the brain alone. The existing gap between human and mouse model studies of extra-cerebellar regions in SCA1 makes it difficult to answer many important questions in the field. This review will cover both the cerebellar and extra-cerebellar effects of SCA1 and highlight the need for further investigations into the impact of mutant ATXN1 expression in these regions. This review will also discuss implications of extra-cerebellar effects not only for SCA1 but other neurodegenerative diseases showing diverse pathology as well.
脊髓小脑性共济失调 1 型（SCA1）是九种多聚谷氨酰胺（polyQ）疾病之一，其特征为成人迟发性、进行性、显性遗传的遗传性疾病。SCA1 是由于 ATXN1 基因中的 CAG 重复数增加，导致 ATAXIN-1 蛋白中的 polyQ 片段扩展而引起的。ATAXIN-1 在大脑中广泛表达。然而，直到最近，SCA1 研究主要集中在小脑，这是因为在患者中观察到特征性的小脑浦肯野细胞丢失，以及 SCA1 患者出现的进行性运动缺陷，包括步态和肢体不协调。然而，SCA1 患者和小鼠模型中还观察到其他症状，如呼吸问题、认知缺陷和记忆障碍、焦虑和抑郁，这表明 SCA1 除了小脑以外还有其他影响，这些影响不能仅仅通过大脑小脑区域的变化来解释。SCA1 中脑外区域的人类和小鼠模型研究之间存在的差距，使得难以回答该领域的许多重要问题。本综述将涵盖 SCA1 的小脑和脑外影响，并强调需要进一步研究这些区域中突变 ATXN1 表达的影响。本综述还将讨论脑外影响的意义，不仅对 SCA1，而且对表现出不同病理学的其他神经退行性疾病也是如此。
