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Etiology of cognitive decline in Spinocerebellar ataxia type 1

1 型脊髓小脑共济失调认知能力下降的病因学

基本信息

批准号：
10449257
负责人：
Marija Cvetanovic
金额：
$ 36.43万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10449257
关键词：
Affect Anatomy Brain Brain region Cells Cerebellar Diseases Cerebellum Chronic Cognition Cognitive Cognitive Therapy Cognitive deficits Data Development Discrimination Disease Electrophysiology (science)Enterobacteria phage P1 Cre recombinase Etiology Exhibits Functional disorder Human Impaired cognition Investigation Knock-in Mouse Lead Life Location LoxP-flanked allele Molecular Morphology Movement Mus Neurocognitive Deficit Neurodegenerative Disorders Neurologic Dysfunctions Neurons Pathogenesis Pathology Patients Phenotype Play Prefrontal Cortex Proteins Purkinje Cells Quality of life Research Reversal Learning Role Slice Testing TimeLine Transgenic Mice Transgenic Organisms Type 1 Spinocerebellar Ataxia ataxin-1 base cell type cognitive development cognitive function cognitive testing conditioned fear effective therapy experimental study imaging approach motor deficit motor impairment mouse model mutant novel polyglutamine public health relevance therapeutic development

项目摘要

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.

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。