Etiology of cognitive decline in Spinocerebellar ataxia type 1

摘要 脊髓小脑性共济失调1型（SCA 1）是一种慢性神经退行性疾病，其特征在于进行性 小脑功能障碍、运动障碍和认知能力下降。对此没有有效的治疗方法 因此，迫切需要增加我们对SCA 1的了解 发病机制SCA 1是由ataxin-1（ATXN 1）中多聚谷氨酰胺（Q）区的异常扩增引起的 蛋白虽然运动缺陷得到了很好的研究，但SCA 1中神经认知缺陷的病因仍然未知。 我们已经开始通过提出两个基本问题来研究SCA 1中神经认知缺陷的病因： ATXN 1突变体在大脑中的位置以及如何表达导致认知缺陷？我们已经 获得的数据强烈表明，突变ATXN 1仅在小脑浦肯野细胞（PC）中表达， 足以导致PC特异性转基因SCA 1小鼠的认知能力下降。然而，相对贡献 小脑和小脑外功能障碍对SCA 1认知缺陷的影响仍然未知。至于如何，我们 初步数据显示SCA 1小鼠前额叶皮层神经元活动的改变，支持以下观点： 前额叶皮层功能异常会导致认知能力下降。此外，我们假设， 小脑对认知缺陷和前额叶皮质功能障碍的贡献更大， 与小脑外区域受到影响的晚期阶段相比， 认知能力下降目前的提议使用新的ATXN 1146 Q/2 Q小鼠来测试这一假设， 我们最近创建的人源化SCA 1小鼠模型。

ABSTRACT Spinocerebellar ataxia type 1 (SCA1) is a chronic neurodegenerative disease characterized by progressive dysfunction of the cerebellum, impaired movement and cognitive decline. No effective treatments exist for this devastating and fatal disease, and thus there is a pressing need to increase our understanding of SCA1 pathogenesis. SCA1 is caused by the abnormal expansion of polyglutamine (Q) region in the ataxin-1 (ATXN1) protein. While motor deficits are well studied, the etiology of neurocognitive deficits in SCA1 remains unknown. We have begun to investigate etiology of the neurocognitive deficits in SCA1 by asking two basic questions: where in the brain and how does expression of mutant ATXN1 lead to cognitive deficits? We have already obtained data that strongly suggest that expression of mutant ATXN1 only in the cerebellar Purkinje cells (PC) is sufficient to cause cognitive decline in PC-specific transgenic SCA1 mice. However, relative contributions of cerebellar and extra-cerebellar dysfunctions to SCA1 cognitive deficits remain unknown. Regarding the how, our preliminary data show alterations in prefrontal cortex neuronal activity in SCA1 mice, supporting the notion that aberrant function of prefrontal cortex contributes to cognitive decline. Moreover, we hypothesize that the extent to which the cerebellum contributes to cognitive deficits and prefrontal cortex dysfunction is larger early in disease compared to late stages when extra-cerebellar regions become affected and are likely to also contribute to cognitive decline. The current proposal tests this hypothesis using floxedATXN1146Q/2Q mice, a novel humanized SCA1 mouse model that we recently created.