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标题：Blockage of MLKL prevents myelin damage in experimental diabetic neuropathy
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作者：Jia Guo ; Zehui Guo ; Yanju Huang 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：14
DOI：10.1073/pnas.2121552119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance Diabetic neuropathy is a commonly occurring complication of diabetes that affects hundreds of millions of patients worldwide. Patients suffering from diabetic neuropathy experience abnormal sensations and have damage in their peripheral nerve axons as well as myelin, a tightly packed Schwann cell sheath that wraps around axons to provide insulation and increases electrical conductivity along the nerve fibers. The molecular events underlying myelin damage in diabetic neuropathy are largely unknown, and there is no efficacious treatment for the disease. The current study, using a diabetic mouse model and human patient nerve samples, uncovered a molecular mechanism underlying myelin sheath damage in diabetic neuropathy and provides a potential treatment strategy for the disease. 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.
关键词：endiabetic neuropathyMLKLmyelin