Decreasing Mutant ATXN1 Nuclear Localization Improves a Spectrum of SCA1-Like Phenotypes and Brain Region Transcriptomic Profiles

Spinocerebellar ataxia type 1 (SCA1) is a dominant trinucleotide repeat neurodegenerative disease characterized by motor dysfunction, cognitive impairment, and premature death. Degeneration of cerebellar Purkinje cells is a frequent and prominent pathological feature of SCA1. We previously showed that transport of ATXN1 to Purkinje cell nuclei is required for pathology, where mutant ATXN1 alters transcription. To examine the role of ATXN1 nuclear localization broadly in SCA1-like disease pathogenesis, CRISPR-Cas9 was used to develop a mouse with an amino acid alteration (K772T) in the nuclear localization sequence of the expanded ATXN1 protein. Characterization of these mice indicates proper nuclear localization of mutant ATXN1 contributes to many disease-like phenotypes including motor dysfunction, cognitive deficits, and premature lethality. RNA sequencing analysis of genes with expression corrected to WT levels in Atxn1175QK772T/2Q mice indicates that transcriptomic aspects of SCA1 pathogenesis differ between the cerebellum, brainstem, cerebral cortex, hippocampus, and striatum. Genetic expression profile comparison (RNA sequencing) of WT, Atxn1175QK772T/2Q, and Atxn1175Q/2Q mouse cerebellum, brainstem, cortex, hippocampus, and striatum at 10 weeks of age and cerebellum, medulla, cortex, hippocampus, and striatum at 26 weeks of age. N=4 mice per genotype at each age.1型脊髓小脑共济失调（Spinocerebellar ataxia type 1, SCA1）是一类显性遗传的三核苷酸重复扩增型神经退行性疾病，以运动功能障碍、认知损害及过早死亡为核心临床特征。小脑浦肯野细胞（cerebellar Purkinje cells）变性是SCA1最为常见且突出的病理表现。本团队前期研究证实，ATXN1向浦肯野细胞核的转运是该病病理发生的必要条件，突变型ATXN1可在细胞核内调控基因转录。为系统性探究ATXN1核定位在SCA1样疾病发病机制中的广泛作用，本研究利用CRISPR-Cas9技术构建了基因工程小鼠模型，该模型中扩增型ATXN1蛋白的核定位序列（nuclear localization sequence）发生了K772T氨基酸改变。对该模型小鼠的表型分析表明，突变型ATXN1的正常核定位可引发多种疾病相关表型，包括运动功能障碍、认知缺陷及过早致死。对Atxn1^175QK772T/2Q小鼠中表达恢复至野生型（wild type, WT）水平的基因进行RNA测序（RNA sequencing）分析后发现，SCA1发病机制的转录组学特征在小脑、脑干、大脑皮层、海马体及纹状体中存在显著差异。本数据集包含不同基因型（野生型、Atxn1^175QK772T/2Q及Atxn1^175Q/2Q）小鼠在10周龄时的小脑、脑干、皮层、海马体及纹状体，以及26周龄时的小脑、延髓、皮层、海马体及纹状体的RNA测序基因表达谱数据。每个年龄组、每个基因型的小鼠样本量均为4只。