Genetics

This post compares three recent MS studies that all put single-cell sequencing at the centre of a metabolic claim, on the question of where the metabolite itself enters the argument. Feng and colleagues paired single-nucleus RNA sequencing with MERFISH on chronic active lesions, finding CD8 T cell niches beside inflamed microglia with an interferon response and raised lipid metabolism, where the lipid half is a transcript signature; they then deleted ABCA1 and ABCG1 in mouse microglia, raising lipid-storing phagocytes, and reduced foam cell formation by targeting sterol metabolism. Xiao and colleagues started from the white matter phenotype of patients with PTS deficiency, showed PTS rising in Olig1-positive cells in MS white matter, and used public human and mouse single-cell datasets to map PTS onto the oligodendrocyte lineage, low in precursors and peaking at immune oligodendroglia; deleting Pts in precursors but not in mature oligodendrocytes lessened disease without touching immunity, acting through HMGCS1 and CYP51, and the authors state that whether the actor is cholesterol, an intermediate metabolite or an enzyme is unresolved. Falk and colleagues ran a clinical trial of four weeks of narrowband UVB in eleven RRMS patients and seven healthy donors, sequencing 384,399 immune cells from skin, blood and cerebrospinal fluid while measuring serum 25-hydroxyvitamin D, which rose less in patients, with the VDR pathway up across lineages and a blunted translation from skin to blood in MS. The closing point is that all three end with testable named genes while, in two of them, the molecule those genes move is still inferred.