Genetics

This post takes CNS resilience in MS down to two metabolites, NAD and fumarate, with most of the evidence coming from human cells rather than from the animal model. It covers the SARM1 dose study in EAE, where the same base-exchange inhibitor cut symptoms at 50 mg/kg and worsened onset and serum neurofilament light chain at 2 mg/kg while two other inhibitor classes did neither. It then covers the human iPSC platform in which rotenone and glutamate injury were rescued by pioglitazone, minocycline and IL-4 but taxol injury was not, with proteomics separating a PPAR-gamma and GSK3-beta arm from a glutathione arm, and no demyelination benefit in cuprizone mice. It closes on the fumarate work, where GPX4 ran at 65 percent of healthy donors in MS patients' blood cells and rose to 175 percent after a year of dimethyl fumarate, yet fell in arthritis fibroblasts whose Nrf2 response was five to ten times larger. Dose, insult and cell type each flip a result.