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

Rivellini, C; Porrello, E; Dina, G; Mrakic-Sposta, S; Vezzoli, A; Bacigaluppi, M; Gullotta, GS; ... Previtali, SC; + view all (2021) JAB1 deletion in oligodendrocytes causes senescence-induced inflammation and neurodegeneration in mice. Journal of Clinical Investigation 10.1172/JCI145071. (In press).

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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.

Type: Article
Title: JAB1 deletion in oligodendrocytes causes senescence-induced inflammation and neurodegeneration in mice
Location: United States
DOI: 10.1172/JCI145071
Publisher version: https://doi.org/10.1172/JCI145071
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Cellular senescence, Demyelinating disorders, Inflammation, Mouse models, Neuroscience
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neuroinflammation
URI: https://discovery.ucl.ac.uk/id/eprint/10140519
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