Abstract
Oligodendrocytes are the primary target of demyelinating disorders, and progressive neurodegenerative changes may evolve in the CNS. DNA damage and oxidative stress are considered key pathogenic events, but the underlying molecular mechanisms remain unclear. Moreover, animal models do not fully recapitulate human diseases, complicating the path to effective treatments. Here we report that mice with cell-autonomous deletion of the nuclear COP9 signalosome component CSN5 (JAB1) in oligodendrocytes develop DNA damage and defective DNA repair in myelinating glial cells. Interestingly, oligodendrocytes lacking JAB1 expression underwent a senescence-like phenotype that fostered chronic inflammation and oxidative stress. These mutants developed progressive CNS demyelination, microglia inflammation, and neurodegeneration, with severe motor deficits and premature death. Notably, blocking microglia inflammation did not prevent neurodegeneration, whereas the deletion of p21CIP1 but not p16INK4a pathway ameliorated the disease. We suggest that senescence is key to sustaining neurodegeneration in demyelinating disorders and may be considered a potential therapeutic target.
Highlights
Myelin is a highly specialized protein and lipid-rich membrane that wraps around axons in the central (CNS) and peripheral nervous system (PNS)
Since oligodendrocytes are sensitive to DNA damage, oxidative stress and perturbation of cell cycle progression, we investigated whether JAB1 in the oligodendrocyte lineage might control CNS myelination and maintenance
JAB1 expressed in oligodendrocytes is required for oligodendrocyte growth and survival To define the role of JAB1 in myelin formation, we generated mutant mice lacking its expression in oligodendrocytes
Summary
Myelin is a highly specialized protein and lipid-rich membrane that wraps around axons in the central (CNS) and peripheral nervous system (PNS). Oligodendrocytes are sensitive to DNA damage and oxidative stress, events that have been associated with progressive axonal loss and are considered to be key elements in MS pathology and many neurodegenerative disorders [8,9,10,11]. Despite their critical role, it is still unclear how DNA damage and oxidative stress are molecularly linked and can foster progressive axonal loss
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