ACSS2 maintains oligodendrocyte progenitor cell pool and is required for myelination during development and aging

The reduction in number and decreased differentiation capacity of oligodendrocyte progenitor cells (OPCs) directly affect myelination in demyelinating diseases and aging, but the underlying mechanisms remain incompletely characterized. Here we observed a marked decline in the number of OPCs during aging, notably within the subpopulation highly expressing Acss2, which encodes acetyl-CoA synthetase 2 (ACSS2). Deletion of ACSS2 in the oligodendrocyte lineage resulted in a reduced OPC population, defective myelinogenesis during development, impaired myelin maintenance in adulthood and aging, and exacerbated age-related cognitive deficits. Mechanistically, ACSS2-mediated acetylation of H4K12 and H3K27 enhances the expression of Gria2, an AMPA receptor subunit critical for OPC proliferation. Furthermore, supplementation with the ACSS2 substrate acetate preserved the number of OPCs, promoted remyelination after injury and improved cognitive function in aged mice. Together, our findings highlight the essential role of ACSS2-mediated acetate utilization in maintaining the OPC population and promoting myelin production during development, demyelination and aging.