Dysregulation of myelin synthesis and actomyosin function underlies aberrant myelin in CMT4B1 neuropathy.

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  • Additional Information
    • Source:
      Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : National Academy of Sciences
    • Subject Terms:
      Signal Transduction*; Charcot-Marie-Tooth Disease/*metabolism ; Myelin Sheath/*metabolism ; Phosphatidylinositol Phosphates/*biosynthesis ; Protein Tyrosine Phosphatases, Non-Receptor/*metabolism; Animals ; Charcot-Marie-Tooth Disease/genetics ; Mechanistic Target of Rapamycin Complex 1/genetics ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Mice ; Mice, Knockout ; Myelin Sheath/genetics ; Myosin Type II/genetics ; Myosin Type II/metabolism ; Phosphatidylinositol Phosphates/genetics ; Protein Tyrosine Phosphatases, Non-Receptor/genetics ; rhoA GTP-Binding Protein/genetics ; rhoA GTP-Binding Protein/metabolism
    • Abstract:
      Charcot-Marie-Tooth type 4B1 (CMT4B1) is a severe autosomal recessive demyelinating neuropathy with childhood onset, caused by loss-of-function mutations in the myotubularin-related 2 ( MTMR2 ) gene. MTMR2 is a ubiquitously expressed catalytically active 3-phosphatase, which in vitro dephosphorylates the 3-phosphoinositides PtdIns3 P and PtdIns(3,5) P 2 , with a preference for PtdIns(3,5) P 2 A hallmark of CMT4B1 neuropathy are redundant loops of myelin in the nerve termed myelin outfoldings, which can be considered the consequence of altered growth of myelinated fibers during postnatal development. How MTMR2 loss and the resulting imbalance of 3'-phosphoinositides cause CMT4B1 is unknown. Here we show that MTMR2 by regulating PtdIns(3,5) P 2 levels coordinates mTORC1-dependent myelin synthesis and RhoA/myosin II-dependent cytoskeletal dynamics to promote myelin membrane expansion and longitudinal myelin growth. Consistent with this, pharmacological inhibition of PtdIns(3,5) P 2 synthesis or mTORC1/RhoA signaling ameliorates CMT4B1 phenotypes. Our data reveal a crucial role for MTMR2-regulated lipid turnover to titrate mTORC1 and RhoA signaling thereby controlling myelin growth.
      Competing Interests: The authors declare no competing interest.
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    • Contributed Indexing:
      Keywords: Charcot-Marie-Tooth neuropathies; Schwann cells; myelin; myotubularin; phosphoinositides
    • Accession Number:
      0 (Phosphatidylinositol Phosphates)
      0 (phosphatidylinositol 3,5-diphosphate)
      EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
      EC 3.1.3.48 (Mtmr2 protein, mouse)
      EC 3.1.3.48 (Protein Tyrosine Phosphatases, Non-Receptor)
      EC 3.6.1.- (Myosin Type II)
      EC 3.6.5.2 (RhoA protein, mouse)
      EC 3.6.5.2 (rhoA GTP-Binding Protein)
    • Subject Terms:
      Charcot-Marie-Tooth disease, Type 4B1
    • Publication Date:
      Date Created: 20210303 Date Completed: 20210816 Latest Revision: 20210903
    • Publication Date:
      20221213
    • Accession Number:
      PMC7958260
    • Accession Number:
      10.1073/pnas.2009469118
    • Accession Number:
      33653949