A Kinase Inside Microglia as an MS Target
Every approved disease-modifying therapy for multiple sclerosis (MS) works on peripheral immunity, and that is also their known limit: once inflammation becomes compartmentalized behind the blood-brain barrier and driven by resident microglia, drugs aimed at circulating lymphocytes have little left to act on. Liu and colleagues went looking for a target inside that compartment rather than outside it, and the gene they landed on is an odd one for neurology. PIM1 is named after the proviral integration site for Moloney murine leukaemia virus, a kinase known mostly from cancer biology. Their claim is that it sits upstream of mitochondrial quality control in microglia, and that blocking it does something that peripheral immunosuppression cannot.
Starting From Patient Tissue Rather Than a Model
The order of the work matters for how much weight the target carries. They began with clinical sample analysis alongside the experimental autoimmune encephalomyelitis model, and found PIM1 significantly upregulated in both, with the signal concentrated in microglia specifically rather than spread across cell types. In patients and in the spinal cords of the animals, that upregulation correlated positively with disease severity and with levels of the proinflammatory cytokines interleukin-1 beta, tumour necrosis factor alpha and interleukin-6. A correlation with severity in human tissue is where a CNS-intrinsic target has to start, because the alternative reading, that the kinase rises as a consequence of damage rather than a contributor, cannot be excluded from the animal data alone.
Four Ways of Interrogating One Kinase
What follows is a deliberately multimodal attack on the same question, and the combination is what makes the result readable. They used pharmacological inhibition with SMI-4a, genetic knockdown of the gene, RNA sequencing to see what moved transcriptionally, and HIS-SIM super-resolution imaging to look at organelles directly. The pharmacology and the knockdown test the same hypothesis through independent failure modes, since a small molecule can hit something other than its nominal target while a knockdown cannot be off-target in the same way. The imaging matters for the same reason: mitophagy is an organelle-scale event, and whether an autophagosome has actually engulfed a mitochondrion is a question conventional microscopy answers poorly. Blocking PIM1 attenuated neuroinflammatory responses and improved clinical symptoms in the animals, while promoting activation of the mitophagy pathway and suppressing inflammation-related molecules.
Two Phosphorylation Sites Pulling Opposite Ways
The mechanism they report is specific enough to be falsifiable, which is more than most proposed targets offer. PIM1 enhances phosphorylation of dynamin-related protein 1 at serine 616 while suppressing its phosphorylation at serine 637. Those two sites push mitochondrial dynamics in opposite directions, so acting on both at once is a stronger intervention than acting on either. The downstream consequence they observed was a breakdown of the clearance machinery: LC3 stopped colocalizing with mitochondria and autophagosome-lysosome fusion was disrupted. In other words the cell could neither tag damaged mitochondria for disposal nor complete the disposal step, which is a failure at two points in one pathway. Dynamin-related protein 1 is the fission machine that divides mitochondria, and division is how a damaged segment gets separated from a healthy network before removal, so a kinase that controls its phosphorylation state sits at the entrance to the whole process.
What Happens to a Microglial Cell That Cannot Clear Mitochondria
The consequences follow in sequence. Mitophagy failed, mitochondrial membrane potential was lost, and reactive oxygen species accumulated. For a microglial cell this is not a quiet metabolic problem, because damaged mitochondria that cannot be cleared are themselves a source of inflammatory signalling, and a cell accumulating reactive oxygen species while sitting in a demyelinated lesion is positioned to do harm to its neighbours rather than to clear debris from them. That is the mechanistic bridge the paper is proposing between a kinase, an organelle, and compartmentalized neuroinflammation, and it is also why the authors describe PIM1 as a candidate for restoring mitochondrial homeostasis rather than for suppressing immunity. The distinction is practical rather than semantic, because a drug that restores clearance in a resident cell would be doing something no currently approved MS therapy attempts.
The Experiment That Ordered the Pathway
One result does more work than the rest, and it is a negative. Giving PIM1 and Drp1 inhibitors together produced no synergistic therapeutic effect. If the two proteins acted through separate routes, combining the inhibitors should have added something; the absence of any addition is what licenses the claim that PIM1 functions as an upstream master regulator of Drp1 rather than as a parallel input. Negative results used this way are how pathway order gets established, and reporting the combination as a null rather than quietly dropping it is the part that makes the hierarchy claim credible instead of asserted. It also has a practical consequence: if PIM1 sits above Drp1, then one inhibitor is the sensible strategy and a combination buys nothing but toxicity.
What This Is and Where It Stops
Read strictly, the paper offers a gene expressed in the right cell type in human MS tissue, correlated with severity there, manipulated two independent ways in an animal model, with a named mechanism at two phosphorylation sites and a combination experiment that orders the pathway. What it does not offer is the thing that would settle it: a human intervention, or evidence that PIM1 in patient microglia behaves as it does in mouse microglia beyond the shared direction of expression. The animal work rests on experimental autoimmune encephalomyelitis, which models the inflammatory phase rather than the compartmentalized one the target is meant to address. The authors position PIM1 as a promising CNS-intrinsic therapeutic target, and promising is the correct word for where the evidence currently sits.
Disclaimer: This blog post is based on the cited study and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Liu, X., Ma, L., Ma, X., Ma, X., Fang, X., Liu, Y., Su, Z., Liu, X., Yu, Z.-L., & Chen, X. (2026). PIM1-induced Drp1 phosphorylation disrupts microglial mitophagy and aggravates neuroinflammation. Pharmacological Research, 230, 108313. https://doi.org/10.1016/j.phrs.2026.108313
