Single-nuclei RNA sequencing uncovers non-cell autonomous changes in cerebellar astrocytes and oligodendrocytes that may contribute to Spinocerebellar Ataxia Type 1 (SCA1) pathogenesis

Abstract

Glial cells, including astrocytes and oligodendrocytes are important for normal brain function. In many neurodegenerative diseases glial cells undergo significant morphological, functional and gene expression changes termed reactive gliosis. The cause, identity and neuroprotective or neurotoxic nature of these changes remains incompletely understood. This knowledge in needed to develop a framework of how individual pathological changes in glial cells contribute to progressive dysfunction and selective neuronal vulnerability in neurodegenerative diseases. This is particularly relevant during the early disease stages that allow for the effective therapies and reversal or slowing of disease phenotypes. Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by an abnormal expansion of CAG repeats in the gene Ataxin1 (ATXN1). While mutant ATXN1 is expressed broadly throughout the brain, SCA1 is characterized by severe degeneration of cerebellar Purkinje cells (PCs). Despite major advances in dissecting the effects of mutant ATXN1 on Purkinje cells, much less is understood how cerebellar astrocytes and oligodendrocytes respond to and contribute to Purkinje cell dysfunction in SCA1. To address this question we performed cerebellar single nuclei RNA sequencing (snRNA seq) of early disease stage Pcp2-ATXN1[82Q] mice, a transgenic SCA1 mouse model expressing mutant ATXN1 only in Purkinje cells. We found no changes in cell numbers in the SCA1 cerebellum. We validated previously indicated pathway and gene expression changes in the Purkinje cells, and identified novel DEG and pathways in Purkinje cells, including Ralyl that may provide compensatory roles and maintain PC function. Importantly we identified profound non-cell autonomous and potentially neuroprotective gene expression and pathway alterations in Bergman glia, velate astrocytes and oligodendrocytes that may contribute to disease pathogenesis.