JAB1 deletion in oligodendrocytes causes senescence-induced inflammation and neurodegeneration in mice
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
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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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 1

Generation of oligodendrocyte-conditional Jab1-null mice.

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Generation of oligodendrocyte-conditional Jab1-null mice. (A) Cnp-Cre Ja...
(A) Cnp-Cre Jab1fl/fl mouse showing reduced size as compared with littermate control. (B) Genotyping PCR using optic nerve–derived DNA providing genomic recombination only in Cnp-Cre Jab1fl/fl mice. (C) qPCR for Cops5 (Jab1) expression in sorted oligodendrocytes (O1+) showing reduced expression in Cnp-Cre Jab1fl/fl as compared with WT mice (*P < 0.05; n = 4; 2-tailed nonparametric Mann-Whitney U test). (D) Western blot analysis and quantification of optic nerve homogenate showing JAB1 reduction in Cnp-Cre Jab1fl/fl mice (****P < 0.0001; n = 6; 1-sample 2-tailed Student’s t test; WT is reported as equal to 1). (E) Confocal images of the corpus callosum (within dashed lines) of Cnp-Cre Jab1fl/fl Rosa26 mice stained for GFP, CC1, NG2, and DAPI. Recombined OPCs positive for GFP and NG2 (arrows) and oligodendrocytes positive for GFP and CC1 (arrowheads) are labeled in the inset magnification. (F) Kaplan-Meier curve showing reduced survival in mutant mice (n = 100 controls and 72 mutants; ****P < 0.0001, χ2 Mantel-Cox test). (G) Mutant mice showing significant body weight reduction over time (*P < 0.05, ***P < 0.001; n = 10; 2-way ANOVA with Bonferroni’s post hoc correction). (H) Rotarod analysis showing significant motor deficits in mutant mice since P40 (****P < 0.0001; 2-tailed nonparametric Mann-Whitney U test). Scale bar: 20 μm; inset, 10 μm.