Targeting pathological cells with senolytic drugs reduces seizures in neurodevelopmental mTOR-related epilepsy.
Journal
Nature neuroscience
ISSN: 1546-1726
Titre abrégé: Nat Neurosci
Pays: United States
ID NLM: 9809671
Informations de publication
Date de publication:
06 May 2024
06 May 2024
Historique:
received:
17
10
2022
accepted:
28
03
2024
medline:
7
5
2024
pubmed:
7
5
2024
entrez:
6
5
2024
Statut:
aheadofprint
Résumé
Cortical malformations such as focal cortical dysplasia type II (FCDII) are associated with pediatric drug-resistant epilepsy that necessitates neurosurgery. FCDII results from somatic mosaicism due to post-zygotic mutations in genes of the PI3K-AKT-mTOR pathway, which produce a subset of dysmorphic cells clustered within healthy brain tissue. Here we show a correlation between epileptiform activity in acute cortical slices obtained from human surgical FCDII brain tissues and the density of dysmorphic neurons. We uncovered multiple signatures of cellular senescence in these pathological cells, including p53/p16 expression, SASP expression and senescence-associated β-galactosidase activity. We also show that administration of senolytic drugs (dasatinib/quercetin) decreases the load of senescent cells and reduces seizure frequency in an Mtor
Identifiants
pubmed: 38710875
doi: 10.1038/s41593-024-01634-2
pii: 10.1038/s41593-024-01634-2
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
ID : 682345
Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
ID : 101113154
Organisme : Agence Nationale de la Recherche (French National Research Agency)
ID : ANR-11-IDEX-0004-02
Organisme : Agence Nationale de la Recherche (French National Research Agency)
ID : ANR-10-IAIHU-06
Organisme : Fondation pour la Recherche Médicale (Foundation for Medical Research in France)
ID : ECO20160736027
Organisme : Fondation pour la Recherche Médicale (Foundation for Medical Research in France)
ID : FDT201904008269
Organisme : Fondation pour la Recherche Médicale (Foundation for Medical Research in France)
ID : FDT202106013286
Informations de copyright
© 2024. The Author(s).
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