GSE184573
CSN5 deletion in oligodendrocytes causes senescence-induced inflammation and neurodegeneration
Oligodendrocytes are the primary target of demyelinating disorders in the CNS, which may evolve in neurodegeneration. DNA damage and oxidative stress are considered key pathogenic events, but the underlying molecular mechanisms remain unclear. Moreover, comprehensive animal models are lacking or do not fully recapitulate human diseases, complicating the path to effective treatments. Here we report that mice with cell autonomous deletion of the COP9 signalosome component CSN5 (Jab1) in oligodendrocytes develop DNA damage and defective DNA repair in myelinating glial cells. Interestingly, oligodendrocytes lacking Jab1 expression undergo a senescence-like phenotype that fosters chronic inflammation and oxidative stress. These mutants develop progressive CNS demyelination, microglia inflammation and neurodegeneration, with severe motor deficits and premature death. Notably, blocking microglia inflammation did not prevent neurodegeneration; whereas, deletion of p21CIP1 but not p16INK4a pathway ameliorated the disease. We suggest that senescence is key to sustaining neurodegeneration in demyelinating disorders and might represent a new potential therapeutic target. Overall design: RNA-Seq of sorted oligodendrocyte (O1+ cells) from P40 mouse brain. 4 Sample per genotype are analyzed (Wt=Control, CnpCre:Jab1fl/fl = KO and p21-/-CnpCre:Jab1fl/fl= dKO) . Each sample derived from two different mouse brains