JAB1 deletion in oligodendrocytes causes senescence-induced inflammation and neurodegeneration in mice.
J Clin Invest
; 132(3)2022 02 01.
Article
en En
| MEDLINE
| ID: mdl-34874913
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Péptido Hidrolasas
/
Envejecimiento
/
Oligodendroglía
/
Eliminación de Gen
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Enfermedades Neurodegenerativas
/
Complejo del Señalosoma COP9
Tipo de estudio:
Etiology_studies
Límite:
Animals
Idioma:
En
Revista:
J Clin Invest
Año:
2022
Tipo del documento:
Article
País de afiliación:
Italia