Genetics

This post covers the study proposing PIM1, a kinase known mostly from cancer biology, as a CNS-intrinsic target in MS, on the grounds that every approved disease-modifying therapy works on peripheral immunity and loses traction once inflammation is compartmentalized behind the blood-brain barrier. It follows the order of the evidence: PIM1 upregulated in microglia in MS patient samples correlating with severity and with IL-1beta, TNF-alpha and IL-6; then pharmacological inhibition with SMI-4a and genetic knockdown as two independent manipulations, with RNA sequencing and HIS-SIM super-resolution imaging; then the mechanism, PIM1 raising Drp1 phosphorylation at Ser616 and suppressing it at Ser637, breaking LC3-mitochondria colocalization and autophagosome-lysosome fusion, so mitophagy fails, membrane potential is lost and reactive oxygen species accumulate. It gives the most weight to a negative result, the absence of synergy when PIM1 and Drp1 inhibitors were combined, which is what orders the pathway, and it states plainly that the animal work rests on the inflammatory model rather than the compartmentalized phase the target is meant for.