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

Abstract Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease mainly characterized by motor incoordination and visual impairment due to progressive cerebellar and retinal degeneration. Alteration of other nervous tissues also contributes to symptoms. The mechanisms underlying motor incoordination of SCA7 remain to be characterized. SCA7 is caused by a polyglutamine (polyQ) expansion in ATXN7, a member of the transcriptional coactivator SAGA complex, which harbors histone modification activities. PolyQ expansion in other proteins is responsible for 5 other SCAs (SCA1-3, 6 and 17). However, the converging and diverging pathophysiological points remain poorly understood. Using a new SCA7 knock-in model carrying 140 glutamines in ATXN7, we analyzed cell-type specific gene expression in the cerebellum. We show that gene deregulation affects all cerebellar cell types, although at variable degree, and correlates with alterations of SAGA-dependent epigenetic marks histone H3 acetylation and H2B ubiquitination. Our results further show that Purkinje cells (PCs) are far the most affected neurons: unlike other cerebellar cell types, PCs show reduced expression of 83 cell-type identity genes, critical for their spontaneous firing activity and synaptic functions. PC gene downregulation precedes morphological alterations, pacemaker dysfunction and motor incoordination. Strikingly, most PC identity genes downregulated in SCA7 mice are also decreased in early symptomatic SCA1 and SCA2 mice, revealing a common signature of early PC pathology 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. Finally, we show that unlike previous SCA7 mouse models, SCA7140Q/5Q mice 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 vision functions. Therefore, SCA7140Q/5Q mice represent an accurate model for the investigation of different aspects of SCA7 pathogenesis.