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
View: Text | PDF
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

×

Figure 6

DNA damage and senescence in mutant mice.

Options: View larger image (or click on image) Download as PowerPoint
DNA damage and senescence in mutant mice. (A) Confocal immunolabeling of...
(A) Confocal immunolabeling of WT and mutant optic nerves stained for CC1 and p-H2AX; quantification shows significant increase of p-H2AX+ oligodendrocytes in mutant mice from P40 (*P < 0.05, **P < 0.01; n = 3–5; 2-tailed nonparametric Mann-Whitney U test). (B) Confocal images of ex vivo optic nerves x-ray–irradiated (IR) to induce DNA damage, stained for DNA-PKcs and CC1; the majority of WT oligodendrocytes (OLs) have nuclear expression of DNA-PK, whereas this percentage is reduced in Jab1–/– optic nerves (**P < 0.01; n = 5; 2-tailed nonparametric Mann-Whitney U test). (C) β-Gal staining and quantification of the corpus callosum and optic nerve from P60 WT and Cnp-Cre Jab1fl/fl mice double-stained with CC1, showing senescent oligodendrocytes in mutant mice (*P < 0.05; n = 5–7; 2-tailed nonparametric Mann-Whitney U test). (D) qPCR for Cdkn2a (p16INK4a) in the optic nerve from WT and Cnp-Cre Jab1fl/fl mice, showing significant increase from P40 (**P < 0.01; n = 5–6; 2-tailed nonparametric Mann-Whitney U test). (E) qPCR for Cdkn1a (p21CIP1) in the optic nerve from WT and Cnp-Cre Jab1fl/fl mice, showing significant increase from P40 (*P < 0.05, **P < 0.01; n = 5–6; 2-tailed nonparametric Mann-Whitney U test). (F) qPCR for SASP in the optic nerve from P60 WT and Cnp-Cre Jab1fl/fl mice, showing significant elevation in mutant mice (*P < 0.05, **P < 0.01; n = 4–6; 2-tailed nonparametric Mann-Whitney U test). (G) Western blot analysis, quantification, and confocal images for HMGB1 in P60 optic nerves of WT and Cnp-Cre Jab1fl/fl mice; HMGB1 is increased in mutant mice and is also translocated in the cytoplasm of mutant oligodendrocytes (arrows) (*P < 0.05; n = 4; 2-tailed nonparametric Mann-Whitney U test). (H) ROS quantification in optic nerve and corpus callosum from WT and Cnp-Cre Jab1fl/fl mice, showing significant ROS elevation from P40 (*P < 0.05, **P < 0.01; n = 3–5; 2-tailed nonparametric Mann-Whitney U test). Scale bars: (A) 40 μm; (B) 2 μm; (C) light microscopy, 50 μm; fluorescence, 2 μm; (G) 20 μm.