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：
10655442
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/10655442
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 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 Transgenic Mice Transgenic Organisms Type 1 Spinocerebellar Ataxia ataxin-1 cell type 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 timeline

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.

抽象的脊椎小脑共济失调1型（SCA1）是一种慢性神经退行性疾病，其特征是进行性疾病小脑功能障碍，运动受损和认知能力下降。没有有效的治疗方法毁灭性和致命疾病，因此需要提高我们对SCA1的理解发病。 SCA1是由双谷氨酰胺（Q）区域在ataxin-1中的异常膨胀引起的（atxn1）蛋白质。尽管对运动缺陷进行了充分的研究，但SCA1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SCA1中神经认知缺陷的病因：突变体ATXN1在大脑中的何处以及如何导致认知缺陷？我们已经获得了强烈表明仅在小脑Purkinje细胞中表达突变体ATXN1的数据（PC）足以引起PC特异性转基因SCA1小鼠的认知能力下降。但是，相对贡献的小脑和针对SCA1认知缺陷的外部功能障碍仍然未知。关于如何，我们的初步数据显示SCA1小鼠前额叶皮层神经元活动的改变，支持这样的观念前额叶皮层的异常功能有助于认知能力下降。此外，我们假设该程度小脑会导致认知缺陷和前额叶皮层功能障碍的早期更大与后期阶段相比，当脑外部地区受到影响时，疾病也可能有助于认知能力下降。当前的提案使用Floxedatxn1146q/2q小鼠对此假设进行了测试，这是一种新颖的我们最近创建的人源化SCA1鼠标模型。