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

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.