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 an SBMA mouse model (AR-97Q). Among all cell types, oligodendrocytes had the highest number of differentially expressed genes before disease onset. Analysis of oligodendrocyte clusters suggested that pathways associated with cation channels and synaptic function were activated before disease onset, with increased output from oligodendrocytes to neurons in AR-97Q mice compared with wild-type mice. These changes in the early stages were abrogated at the advanced stages. An oligodendrocyte model of SBMA showed phenotypes similar to those of AR-97Q mice at early stages, such as increased transcriptional changes in synapse organization, and Ca2+ imaging of oligodendrocytes in AR-97Q mice revealed the increased Ca2+ responses. A coculture system of primary rat oligodendrocytes and neurons revealed that the mutant AR in oligodendrocytes affected the activity and synchronization of neurons. These findings suggest that dysregulated cell-to-cell communication plays a critical role in early SBMA pathology and that synaptic or ion channel-related proteins, such as contactin associated protein 2 (Cntnap2) and NALCN channel auxiliary factor 1 (Fam155a), are potential therapeutic targets for SBMA.