脊髓小脑共济失调7型(SCA7)是一种遗传性神经退行性疾病,主要表现为进行性小脑变性导致的运动不协调。SCA7是由ATXN7中的多聚谷氨酰胺扩增引起的,ATXN7是转录共激活子SAGA的一个亚基,藏有组蛋白修饰活动。特定蛋白质中的聚谷氨酰胺扩增也负责SCA1-SCA3,SCA6和SCA17;然而,收敛和发散的病理机制仍然知之甚少。使用新的SCA7敲入鼠标,SCA7140Q/5Q,我们分析了小脑中的基因表达,并使用已发表的数据集将基因失调分配给特定的细胞类型。基因失调影响所有的小脑细胞类型,尽管在不同程度上,并与SAGA依赖性表观遗传标记的改变相关。Purkinje细胞(PC)是迄今为止受影响最严重的神经元,并显示83个细胞型身份基因的表达减少,包括对其自发放电活动和突触功能至关重要的这些。PC基因下调先于形态学改变,起搏器功能障碍,电机不协调。引人注目的是,SCA7中下调的大多数PC基因在SCA1和SCA2小鼠中的表达也降低,揭示融合的病理机制和常见的疾病特征,涉及cGMP-PKG和磷脂酰肌醇信号通路和LTD。因此,我们的研究指出了治疗发展的分子靶标,这可能对几个SCA有益。此外,我们显示SCA7140Q/5Q男性和女性表现出患者中观察到的主要疾病特征,包括小脑损伤,脑萎缩,周围神经病理学,和光感受器营养不良,解释了行为的进行性损害,电机,和视觉功能。SCA7140Q/5Q小鼠代表了用于研究SCA7发病机理的不同方面的准确模型。重要声明脊髓小脑共济失调7(SCA7)是几种以小脑变性为特征的遗传性SCA之一,因为特定蛋白质中聚谷氨酰胺的扩增。参与SCA7的ATXN7是SAGA转录共激活子复合物的亚基。为了了解SCA7的发病机制,我们确定了SCA7小鼠小脑中细胞类型特异性基因的失调。我们发现Purkinje细胞是受影响最大的小脑细胞类型,并显示出神经元身份基因的一大子集的下调,对它们的自发放电和突触功能至关重要。引人注目的是,在另外两种SCA的小鼠模型中,相同的Purkinje细胞基因被下调。因此,我们的工作揭示了几种SCA共有的疾病特征,并揭示了其治疗的潜在分子靶点.
Spinocerebellar ataxia type 7 (
SCA7) is an inherited neurodegenerative disease mainly characterized by motor incoordination because of 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-SCA3, SCA6, and SCA17; 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 morphologic 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 LTD. 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 pathogenesis.SIGNIFICANCE STATEMENT Spinocerebellar ataxia 7 (SCA7) is one of the several forms of inherited SCAs characterized by cerebellar degeneration because of polyglutamine expansion in specific proteins. The ATXN7 involved in
SCA7 is a subunit of SAGA transcriptional coactivator complex. To understand the pathomechanisms of SCA7, we determined the cell type-specific gene deregulation in
SCA7 mouse cerebellum. We found that the Purkinje cells are the most affected cerebellar cell type and show downregulation of a large subset of neuronal identity genes, critical for their spontaneous firing and synaptic functions. Strikingly, the same Purkinje cell genes are downregulated in mouse models of two other SCAs. Thus, our work reveals a disease signature shared among several SCAs and uncovers potential molecular targets for their treatment.