Fiche publication
Date publication
février 2026
Journal
Cell reports. Medicine
Auteurs
Membres identifiés du Cancéropôle Est :
Pr GUEANT Jean-Louis
,
Dr COELHO David
,
Dr HERGALANT Sébastien
Tous les auteurs :
Matmat K, Hassan Z, Pourié G, Atlasi Y, Seal SV, Jeandel M, Arnold C, Luharia S, Umoret R, Safar R, Heinken A, Alberto JM, Baspinar O, Paoli J, Hergalant S, Rouyer P, Camadro JM, Lignières L, Coelho D, Guéant JL, Guéant-Rodriguez RM
Lien Pubmed
Résumé
Inborn errors of vitamin B12 metabolism (IECM) resulting from impaired methionine synthase (MTR) activity cause severe cognitive and neurological deficits that remain unresponsive to conventional B12 supplementation. Using a brain-specific Mtr knockout mouse model, we identify the NAD-dependent deacetylase SIRT1 as a central regulator of the pathological phenotype and evaluate the therapeutic efficacy of its pharmacological activator SRT2104. MS deficiency induces profound metabolic, mitochondrial, and epigenomic alterations in the hippocampus, including promoter hypermethylation of the pyruvate dehydrogenase complex, impaired tricarboxylic acid (TCA) cycle activity, and reduced SIRT1 expression. At the functional level, we observe disrupted Wnt signaling associated with decreased neurogenesis, increased astrocytosis, and cognitive impairment. SRT2104 treatment restores mitochondrial and energy metabolism, normalizes Wnt signaling and neurogenesis markers, and rescues learning and memory performance. These findings identify SIRT1 as a therapeutic target in B12-related neurodevelopmental disorders and support the clinical repurposing of SRT2104 to alleviate persistent neurological symptoms.
Mots clés
SIRT1, Wnt signaling, drug repurposing, energy metabolism, inborn errors of cobalamin metabolism, methionine synthase, neurodevelopment, neurogenesis, one-carbon metabolism, vitamin B12 deficiency
Référence
Cell Rep Med. 2026 02 25;:102643
