Dietary Folic Acid Rescues Peripheral Neuropathy in mice models of neural tube defects and type 2 diabetes

Folate-mediated one-carbon metabolism is implicated in several pathologies including neural tube defects, cancer and neurodegenerative disorders. Mice with reduced Shmt1 expression are viable and thrive, but are sensitized to low penetrant, folic acid (FA) dependent neural tube defects (NTDs) and impaired de novo thymidylate synthesis. To determine if risk for neural tube defects shared similar etiology for risk of peripheral neuropathy (PN), nerve conduction velocity was assessed in Shmt1+/- and Shmt1-/- mice. Mice with reduced Shmt1 expression exhibited congenital PN, with greater severity in females compared to males. The neuropathic progression was distinct from diabetic peripheral neuropathy (DPN) as seen in the diabetic (Leprdb) mice. Mice on excess folic acid diet showed a rescue trend for PN phenotype in both Shmt1-/- and Leprdb/db mice. Further, we investigated transcriptome from L3-L5 dorsal root ganglia (DRG) which revealed sex-specific glial cell gene expression pattern between Shmt1+/+ and Shmt1-/- mice. Transcriptome analyses also showed excess dietary folic acid inhibits neuronal voltage gated ion channels (VGCCs) and regulates calcium homeostasis possibly rescuing PN in Shmt1-/- females. Lastly, we also report, dietary uridine directly causes demyelinating PN in mice independent of genotype or folate status. Taken together, our findings warrant further research to understand a complex disorder like PN and recommend precision dietary and therapeutic approaches based on the origin. For the RNA-seq experiments, wild type (Shmt1+/+) and knockout (Shmt1-/-) female and male mice were randomly weaned to AIN-93G (control) diet. For the rescue arm of the study, Shmt1-/- female mice were weaned to AIN-93G diet supplemented with 8mg/kg Folic Acid (excess FA) diets. The number of mice in each diet group were 5. After six months, dorsal root ganglions (DRGs) were surgically extracted from left and right sides of L3-L5 region of the spinal column. Total mRNA was extracted from the combined L3-L5 DRGs from each mice and represent an individual data point replicate in the RNA-seq data for analysis.