Dysregulated synaptic gene expression in oligodendrocytes of spinal and bulbar muscular atrophy

Abstract

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by an expanded CAG repeat in the androgen receptor (AR) gene. To elucidate the cell type-specific temporal gene expression in SBMA, we performed single-nucleus RNA sequencing on the spinal cords of AR-97Q mice. Among all cell types, oligodendrocytes (OLs) had the highest number of differentially expressed genes before disease onset. Analysis of OL clusters suggested that pathways associated with cation channels and synaptic function were activated before disease onset, with increased output from OLs to neurons in AR-97Q mice compared to wild-type mice. These changes in the early stages were abrogated in the advanced stages. An OL cell model of SBMA showed phenotypes similar to those of AR-97Q mice at early stages, such as increased transcriptional changes in synapse organization. Our results indicate that the dysregulation of cell-to-cell communication has a major impact on the early pathology of SBMA and is a potential therapeutic target for SBMA.