2. Academic Validation
  3. ACSS2 maintains oligodendrocyte progenitor cell pool and is required for myelination during development and aging

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

  • Nat Aging. 2026 Mar;6(3):560-578. doi: 10.1038/s43587-026-01071-9.
Weijie Gao # 1 2,  Siyi Chen # 1 2,  Yufei Huang 1 2,  Xin Wu 1 2,  Lvping Zhuang 1,  Yuying Zheng 1 2,  Xiaoman Dai 1,  Ying Fu 3,  Wanjin Chen 1 3,  Qinyong Ye 1,  Xiaochun Chen 4,  Jing Zhang 5
Affiliations

Affiliations

  • 1 Department of Neurology, Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology and Institute of Neuroscience, Fujian Medical University, Fuzhou, China.
  • 2 The School of Basic Medical Sciences, Public Technology Service Center, Fujian Medical University, Fuzhou, China.
  • 3 Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
  • 4 Department of Neurology, Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology and Institute of Neuroscience, Fujian Medical University, Fuzhou, China. [email protected].
  • 5 Department of Neurology, Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology and Institute of Neuroscience, Fujian Medical University, Fuzhou, China. [email protected].
  • # Contributed equally.
PMID: 41781676 DOI: 10.1038/s43587-026-01071-9
Abstract

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.

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