Dietary folic acid prevents peripheral neuropathy in mouse models of neural tube defects and type 2 diabetes

Folate-mediated one-carbon metabolism is implicated in several pathologies including neural tube defects (NTDs), cancer and neurodegenerative disorders, whereas diabetes is associated with NTDs and peripheral neuropathy (PN). The development of peripheral neuropathy was assessed in Shmt1+/- and Shmt1 -/- mice, which are models of human folic acid-responsive NTDs, and diabetic (Leprdb) mice to determine if NTDs and PN have a shared etiology. From 6 weeks of age, male and female mice with reduced Shmt1 expression exhibited PN, with greater severity in females compared to males. The neuropathic progression was distinct from diabetic peripheral neuropathy (DPN) observed in Leprdb mice. Excess dietary folic acid prevented PN in both Shmt1-/- and Leprdb/db mice, whereas dietary uridine caused demyelinating PN in mice independent of genotype and folate status. The transcriptome from L3-L5 dorsal root ganglia (DRG) exhibited distinct sex-specific differences in glial cell gene expression when comparing Shmt1+/+ and Shmt1-/- mice. DRG sensory neurons exhibited changes in the expression of solute carriers and ion channels involved in nociception, neurotransmission and structural support. We conclude that reduced thymidylate synthesis causes folic-acid responsive NTDs and PN in mice, and that diabetes sensitizes mice to folic acid-responsive PN. Diabetes induces a special nutritional requirement for high intake of folic acid to prevent PN. Overall design: 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.