Inversely proportional myelin growth due to altered Pmp22 gene dosage identifies PI3K/Akt/mTOR signaling as a novel therapeutic target in HNPP
Inversely proportional myelin growth due to altered Pmp22 gene dosage identifies PI3K/Akt/mTOR signaling as a novel therapeutic target in HNPP
Abstract Duplication of the gene encoding the myelin protein PMP22 causes the hereditary neuropathy Charcot-Marie-Tooth disease 1A (CMT1A), characterized by hypomyelination of medium to large caliber peripheral axons. Conversely, haplo-insufficiency of PMP22 leads to focal myelin overgrowth in hereditary neuropathy with liability to pressure palsies (HNPP). However, the molecular mechanisms of myelin growth regulation by PMP22 remain obscure. Here, we found that the major inhibitor of the myelin growth signaling pathway PI3K/Akt/mTOR, phosphatase and tensin homolog (PTEN) is increased in abundance in CMT1A and decreased in HNPP rodent models. Indeed, treatment of DRG co-cultures from HNPP mice with PI3K/Akt/mTOR pathway inhibitors reduced focal hypermyelination and, importantly, treatment of HNPP mice with the mTOR inhibitor Rapamycin improved motor behavior, increased compound muscle amplitudes (CMAP) and reduced tomacula formation in the peripheral nerve. In Pmp22tg CMT1A mice, we uncovered that the differentiation defect of Schwann cells is independent from PI3K/Akt/mTOR activity, rendering the pathway insufficient as a therapy target on its own. Thus, while CMT1A pathogenesis is governed by dys-differentiation uncoupled from PI3K/Akt/mTOR signaling, targeting the pathway provides novel proof-of-principle for a therapeutic approach to HNPP.
Hartmann Timon J、Ewers David、Fledrich Robert、Goebbels Sandra、Nave Klaus-Armin、Krauter Doris、Sereda Michael W、Kungl Theresa、Volkmann Stefan
Max-Planck Institute of Experimental Medicine, Department of NeurogeneticsMax-Planck Institute of Experimental Medicine, Department of Neurogenetics||Max-Planck Institute of Experimental Medicine, Research Group ?°Translational Neurogenetics?±||University Medical Center G?ttingen, Department of NeurologyUniversity of Leipzig, Institute of AnatomyMax-Planck Institute of Experimental Medicine, Department of NeurogeneticsMax-Planck Institute of Experimental Medicine, Department of NeurogeneticsMax-Planck Institute of Experimental Medicine, Department of Neurogenetics||Max-Planck Institute of Experimental Medicine, Research Group ?°Translational Neurogenetics?±||University Medical Center G?ttingen, Department of NeurologyMax-Planck Institute of Experimental Medicine, Department of Neurogenetics||Max-Planck Institute of Experimental Medicine, Research Group ?°Translational Neurogenetics?±||University Medical Center G?ttingen, Department of NeurologyUniversity of Leipzig, Institute of AnatomyMax-Planck Institute of Experimental Medicine, Department of Neurogenetics
神经病学、精神病学基础医学分子生物学
Hartmann Timon J,Ewers David,Fledrich Robert,Goebbels Sandra,Nave Klaus-Armin,Krauter Doris,Sereda Michael W,Kungl Theresa,Volkmann Stefan.Inversely proportional myelin growth due to altered Pmp22 gene dosage identifies PI3K/Akt/mTOR signaling as a novel therapeutic target in HNPP[EB/OL].(2025-03-28)[2025-05-28].https://www.biorxiv.org/content/10.1101/2021.11.08.467756.点此复制
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