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SIRT1 mediates brain metabolic and developmental consequences of methionine synthase deficiency in inborn errors of cobalamin metabolism

ABSTRACT: Inborn errors of vitamin B12 metabolism (IECM) resulting from impaired methionine synthase (MS, encoded by MTR) activity cause severe cognitive and neurological deficits that are often unresponsive to conventional B12 supplementation. Using a brain-specific Mtr knockout mouse model, we identified the NAD⁺-dependent deacetylase SIRT1 as a central regulator of the pathological phenotype, and evaluated the therapeutic efficacy of its pharmacological activator, SRT2104. MS deficiency led to profound metabolic, mitochondrial, and epigenomic alterations in the hippocampus, including promoter hypermethylation of the pyruvate dehydrogenase complex, impaired TCA cycle activity, and reduced SIRT1 expression. At the functional level, we observed a disruption of Wnt signaling, associated with decreased neurogenesis, increased astrocytosis, and cognitive impairment. Treatment with SRT2104 effectively restored mitochondrial and energy metabolism, normalized Wnt signaling and neurogenesis markers, and rescued learning and memory performance. These findings identify SIRT1 as a potential therapeutic target in B12-related neurodevelopmental disorders and support the clinical repurposing of SRT2104 to alleviate persistent neurological symptoms.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Guillaume CHEVREUX

LAB HEAD: GUEANT-RODRIGUEZ, Rosa-Maria

PROVIDER: PXD071487 | Pride | 2026-01-06

REPOSITORIES: Pride

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			Action	DRS
	2220002-1-K33-Male-WT_S1-D5_1_2961.d.refined.mgf	Mgf
	2220002-2-K43-Male-KO_S1-D7_1_2963.d.refined.mgf	Mgf
	2220002-3-K40-Femelle-WT_S1-D9_1_2965.d.refined.mgf	Mgf
	2220002-4-K41-Femelle-KO_S1-D11_1_2967.d.refined.mgf	Mgf
	2220002-5-K35-Male-WT_S1-E1_1_2969.d.refined.mgf	Mgf

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SIRT1 mediates brain metabolic and developmental consequences of methionine synthase deficiency in inborn errors of cobalamin metabolism

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