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 5

Depletion of microglia activation does not ameliorate neurodegeneration in Jab1-mutant mice.

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Depletion of microglia activation does not ameliorate neurodegeneration ...
(A) Electron micrographs of transverse sections of P50 optic nerve from WT, CCR2–/–, Cnp-Cre Jab1fl/fl, and Cnp-Cre Jab1fl/fl CCR2–/– mice and relative quantification of IBA1+ cells and numbers of myelinated fibers and degenerating fibers, showing no significant differences between Jab1–/– and double-mutant Jab1–/– CCR2–/– mice (**P < 0.01, ***P < 0.001; n = 4–5; 1-way ANOVA with Bonferroni’s multiple-comparison test). (B) Confocal images (for IBA1 and MBP) and electron micrographs of P41 optic nerve from WT and Cnp-Cre Jab1fl/fl mice treated (PLX +) or not (PLX –) for 21 days with PLX3397 (see schematic) and relative quantification of IBA1+ cells and numbers of myelinated and degenerating fibers. Although the number of IBA1+ cells was significantly reduced in PLX-treated mice, no differences in the numbers of myelinated and degenerating fibers were observed (*P < 0.05, **P < 0.01, ***P < 0.001; n = 4–9; 1-way ANOVA with Bonferroni’s multiple-comparison test). Scale bars: (A) 1 μm; (B) immunohistochemistry, 40 μm; electron microscopy, 2 μm.