Etiology of cognitive decline in Spinocerebellar ataxia type 1

摘要 脊髓小脑性共济失调1型(SCA1)是一种以进行性为特征的慢性神经退行性疾病 小脑功能障碍、运动障碍和认知能力下降。目前尚无有效的治疗方法。 毁灭性和致命性疾病，因此迫切需要增加我们对SCA1的理解 发病机制。SCA1是由ataxin-1(ATXN1)中多聚谷氨酰胺(Q)区的异常扩张引起的 蛋白。虽然运动障碍已经得到了很好的研究，但SCA1神经认知障碍的病因仍不清楚。 我们已经开始通过提出两个基本问题来研究SCA1神经认知缺陷的病因学： 突变型ATXN1在大脑的哪个部位表达会导致认知缺陷？我们已经这么做了 获得的数据有力地表明，突变的ATXN1仅在小脑浦肯野细胞(PC)中表达 足以导致PC特异性转基因SCA1小鼠的认知能力下降。然而，相对贡献是 SCA1认知缺陷的小脑和小脑外功能障碍尚不清楚。关于如何，我们的 初步数据显示，SCA1小鼠前额叶皮质神经元活动发生变化，支持这一观点 前额叶皮质功能异常是认知功能下降的原因之一。此外，我们假设， 其中小脑导致认知障碍，前额叶皮质功能障碍在早期较大 疾病与晚期相比，当小脑外区域受到影响并可能也起作用时 导致认知能力下降。目前的建议是使用一种新型的FloxedATXN1146Q/2Q小鼠来验证这一假设 我们最近创建的人源化SCA1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.