JAB1 deletion in oligodendrocytes causes senescence-induced inflammation and neurodegeneration in mice
Cristina Rivellini, … , Angelo Quattrini, Stefano C. Previtali
Cristina Rivellini, … , Angelo Quattrini, Stefano C. Previtali
Published December 7, 2021
Citation Information: J Clin Invest. 2022;132(3):e145071. https://doi.org/10.1172/JCI145071.
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Research Article Inflammation Neuroscience

JAB1 deletion in oligodendrocytes causes senescence-induced inflammation and neurodegeneration in mice

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.

Authors

Cristina Rivellini, Emanuela Porrello, Giorgia Dina, Simona Mrakic-Sposta, Alessandra Vezzoli, Marco Bacigaluppi, Giorgia Serena Gullotta, Linda Chaabane, Letizia Leocani, Silvia Marenna, Emanuela Colombo, Cinthia Farina, Jia Newcombe, Klaus-Armin Nave, Ruggero Pardi, Angelo Quattrini, Stefano C. Previtali

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Figure 4

Inflammatory infiltration in Jab1-mutant mice.

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Inflammatory infiltration in Jab1-mutant mice. (A) Immunolabeling of WT ...
(A) Immunolabeling of WT and Cnp-Cre Jab1fl/fl optic nerves for IBA1 and MBP at ages P60 and P90 and relative quantification from P20 to P90, showing progressive increase in the number of IBA1+ cells in mutant mice (*P < 0.05, **P < 0.01; n = 3–5; 2-tailed nonparametric Mann-Whitney U test). (B) FACS analysis of P60 WT and Cnp-Cre Jab1fl/fl brain for CD45, CD11b (representative plots), CD11c, Ly6G, and Ly6C, showing quantification of microglia, activated microglia, lymphocytes, monocytes, macrophages, and neutrophils (**P < 0.01, ***P < 0.001; n = 13 WT, n = 9 Cnp-Cre Jab1fl/fl; 2-tailed nonparametric Mann-Whitney U test). (C) Immunolabeling for GFAP and CC1 of the optic nerve from WT and Cnp-Cre Jab1fl/fl mice at age P60 and relative quantification, showing increased number of GFAP+ reactive astrocytes in mutant mice (*P < 0.05; n = 4; 2-tailed nonparametric Mann-Whitney U test). Scale bars: (A and C) 40 μm.