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 3

Longitudinal MRI and VEP evaluation.

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Longitudinal MRI and VEP evaluation. (A) Brain MT MRI images of WT and C...
(A) Brain MT MRI images of WT and Cnp-Cre Jab1fl/fl mice at different ages (P30, P45, and P65). While in WT mice, the corpus callosum is clearly delineated on MT images (in dark, arrows), it is hardly distinguishable in Jab1-mutant mice, in which the contrast is similar at the first exam (P30) and becomes hyperintense at later stages (P45 and P60, arrows). (B) With DTI (color map of FA), the corpus callosum is well discriminated in all the animals, but the FA (color map) is clearly decreased at P45 and P60 in Jab1-mutant as compared with WT mice (arrows). (C) Quantitative analysis of MT and FA measured in the medial of the corpus callosum. Both MT and FA were significantly reduced with age in Jab1-mutant mice as compared with healthy controls (*P < 0.05, ***P < 0.001; n = 6; 2-way ANOVA with Bonferroni’s post hoc correction). (D) N1 latency and amplitude measured in WT and Cnp-Cre Jab1fl/fl mice at age P30, P45, and P65 (****P < 0.0001; n = 7 WT, 6 mutant; 2-way ANOVA with Bonferroni’s post hoc correction). (E) Representative VEP waveforms recorded from WT and Cnp-Cre Jab1fl/fl at different ages. Horizontal bar, 50 ms; vertical bar, 20 μV.