SIRT1 is a therapeutic target of brain metabolic and developmental consequences of methionine synthase deficiency in inborn errors of cobalamin metabolism

Inborn errors of vitamin B12 metabolism (IECM) with impaired methionine synthase (MS) activity (encoded by MTR), manifest severe cognitive and neurological symptoms unresponsive to B12 therapy. We explored the effects of Mtr brain-selective deletion at postnatal stage in mouse, identified histone deacetylase SIRT1 as a target of innovative therapy and evaluated the SRT2104 SIRT1 pharmacological activator to reverse alterations. We observed hippocampal significant metabolomic, behavioral, epigenome-wide, and proteomic alterations with promoter hypermethylation of pyruvate dehydrogenase and an abolished expression of SIRT1. MS disrupted the SIRT1/Wnt axis, with decreased neurogenesis and increased astrocytosis associated with altered learning abilities in water maze. Treatment with SRT2104 reversed the alterations of TCA, neurogenesis/astrocytosis and cognition. Our data highlight the prominent role of SIRT1 in brain neurodevelopmental and metabolic alterations of IECM, and the SRT2104 SIRT1 pharmacological activator as a promising drug repurposing candidate to treat B12-IECM resistant neurological manifestations.