Blockage of MLKL prevents myelin damage in experimental diabetic neuropathy

Demyelination is a pathological feature of diabetic neuropathy, a common and painful complication of diabetes, yet the mechanisms underlying diabetes-induced demyelination remain unclear. Here, we show that targeting mixed lineage kinase domain-like protein (MLKL), a protein critical in necroptosis, using Schwann cell-specific genetic knockout, S441A single-amino acid knockin mutation, or pharmacological inhibition all blocked myelin sheath decompaction and prevented the decrease of nerve conduction velocity in streptozotocin-induced diabetic mice. The decompaction of the myelin sheaths of sural nerves was observed in biopsy samples from diabetic patients, and the MLKL-mediated myelin breakdown was activated in human diabetic neuropathy patients. Our study establishes a direct myelin degradation-related role for MLKL in diabetic neuropathy and defines MLKL as a druggable target for developing agents to prevent or treat diabetic neuropathy.