SCA7 mouse cerebellar pathology reveals preferential downregulation of key Purkinje cell-identity genes and shared disease signature with SCA1 and SCA2

Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease mainly characterized by motor incoordination due to progressive cerebellar degeneration. SCA7 is caused by polyglutamine expansion in ATXN7, a subunit of the transcriptional coactivator SAGA, which harbors histone modification activities. Polyglutamine expansions in specific proteins are also responsible for SCA1-3, 6 and 17, however, the converging and diverging pathomechanisms remain poorly understood. Using a new SCA7 knock-in mouse, SCA7140Q/5Q, we analyzed gene expression in the cerebellum and assigned gene deregulation to specific cell types using published datasets. Gene deregulation affects all cerebellar cell types, although at variable degree, and correlates with alterations of SAGA-dependent epigenetic marks. Purkinje cells (PCs) are by far the most affected neurons and show reduced expression of 83 cell-type identity genes, including these critical for their spontaneous firing activity and synaptic functions. PC gene downregulation precedes morphological alterations, pacemaker dysfunction and motor incoordination. Strikingly, most PC genes downregulated in SCA7 have also decreased expression in SCA1 and SCA2 mice, revealing converging pathomechanisms and a common disease signature involving cGMP-PKG and phosphatidylinositol signaling pathways and long-term depression. Our study thus points out molecular targets for therapeutic development, which may prove beneficial for several SCAs. Furthermore, we show that SCA7140Q/5Q males and females exhibit the major disease features observed in patients, including cerebellar damage, cerebral atrophy, peripheral nerves pathology and photoreceptor dystrophy, which account for progressive impairment of behavior, motor and visual functions. SCA7140Q/5Q mice represent an accurate model for the investigation of different aspects of SCA7. Overall design: Cerebellar transcriptional profiling (RNA-seq) of a knock-in mouse model of Spinocerebellar Ataxia Type 7 (SCA7).

7型脊髓小脑共济失调（Spinocerebellar ataxia type 7, SCA7）是一种遗传性神经退行性疾病，核心特征为进行性小脑变性所致的运动协调障碍。SCA7由转录共激活因子SAGA的亚基共济失调蛋白7（ATXN7）发生多聚谷氨酰胺扩增引发，该复合物具备组蛋白修饰活性。特定蛋白的多聚谷氨酰胺扩增同样可导致1~3、6及17型脊髓小脑共济失调，但二者的趋同与分歧致病机制仍不甚明确。本研究利用新型SCA7敲入小鼠模型SCA7140Q/5Q，对小脑的基因表达谱进行分析，并借助已发表数据集将基因失调归因于特定细胞类型。研究发现，基因失调累及所有小脑细胞类型（尽管程度存在差异），且与SAGA依赖的表观遗传标记改变相关。浦肯野细胞（Purkinje cells, PCs）是受影响最显著的神经元，其83个细胞类型特征基因的表达水平降低，其中包括对其自发放电活性及突触功能至关重要的基因。浦肯野细胞的基因下调先于形态改变、起搏功能障碍及运动协调障碍出现。值得注意的是，SCA7模型中下调的多数浦肯野细胞基因在SCA1及SCA2小鼠中同样表达降低，这揭示了二者的趋同致病机制，以及涉及cGMP-PKG与磷脂酰肌醇信号通路、长时程抑制的共同疾病特征。本研究由此确定了可用于治疗开发的分子靶点，该靶点或对多种脊髓小脑共济失调均有效。此外，本研究证实SCA7140Q/5Q小鼠的雌雄个体均呈现患者中观察到的主要疾病特征，包括小脑损伤、大脑萎缩、周围神经病变及光感受器营养不良，这些病理改变可导致行为、运动及视觉功能进行性受损。SCA7140Q/5Q小鼠是研究SCA7不同方面的精准模型。整体实验设计：对7型脊髓小脑共济失调（SCA7）敲入小鼠模型的小脑进行转录组测序（RNA-seq）分析。