Loss of Ms4a6c Ameliorates Male tgSOD1G93A Defects and Reveals Sexual Dimorphic Pathology

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal, non-cell autonomous neurodegenerative disease targeting motor neurons (MN) that has a higher prevalence in males than in females. The MS4A gene cluster, including MS4A6A, has been associated with Alzheimer’s Disease in genome-wide association studies and is expressed in CNS myeloid cells. Here, we find MS4A6A is upregulated in human ALS spinal cord tissue along with its mouse ortholog, Ms4a6c, which is upregulated in spinal cords of the tgSOD1G93A mouse model. We find that knocking out Ms4a6c in tgSOD1G93A mice delays disease progression and extends survival in a male-specific manner. Through histological and transcriptional analyses, Ma4s6c-/- also improved MN loss and astrogliosis in males. Disease associated microglial expression and inflammation were reduced in both sexes by Ma4s6c knock-out. RNA sequencing of spinal cord tissue revealed a sexually dimorphic expression profile in tgSOD1G93A mice both with and without the Ma4s6c gene. In male but not female tgSOD1G93A Ma4s6c-/- mice, genes involved in angiogenesis and blood spinal cord barrier maintenance were over-represented as compared to tgSOD1G93A mice. Altogether, these findings implicate Ms4a6c in ALS and demonstrate fundamental sex differences that may play a role in the sex bias occurring in ALS.