title: Dynamin 2 mutations in Charcot-Marie-Tooth neuropathy highlight the importance of clathrin-mediated endocytosis in myelination.
abstract: Mutations in dynamin 2 (DNM2) lead to dominant intermediate Charcot-Marie-Tooth neuropathy type B, while a different set of DNM2 mutations cause autosomal dominant centronuclear myopathy. In this study, we aimed to elucidate the disease mechanisms in dominant intermediate Charcot-Marie-Tooth neuropathy type B and to find explanations for the tissue-specific defects that are associated with different DNM2 mutations in dominant intermediate Charcot-Marie-Tooth neuropathy type B versus autosomal dominant centronuclear myopathy. We used tissue derived from Dnm2-deficient mice to establish an appropriate peripheral nerve model and found that dominant intermediate Charcot-Marie-Tooth neuropathy type B-associated dynamin 2 mutants, but not autosomal dominant centronuclear myopathy mutants, impaired myelination. In contrast to autosomal dominant centronuclear myopathy mutants, Schwann cells and neurons from the peripheral nervous system expressing dominant intermediate Charcot-Marie-Tooth neuropathy mutants showed defects in clathrin-mediated endocytosis. We demonstrate that, as a consequence, protein surface levels are altered in Schwann cells. Furthermore, we discovered that myelination is strictly dependent on Dnm2 and clathrin-mediated endocytosis function. Thus, we propose that altered endocytosis is a major contributing factor to the disease mechanisms in dominant intermediate Charcot-Marie-Tooth neuropathy type B.
authors.affiliation: Institute of Molecular Health Sciences, Chair in Cell Biology, ETH Zurich, ETH-Hönggerberg, Schafmattstrasse 18, Zurich, Switzerland.
authors.forename: Páris N M
authors.initials: PN
authors.lastname: Sidiropoulos
authors.forename: Michaela
authors.initials: M
authors.lastname: Miehe
authors.forename: Thomas
authors.initials: T
authors.lastname: Bock
authors.forename: Elisa
authors.initials: E
authors.lastname: Tinelli
authors.forename: Carole I
authors.initials: CI
authors.lastname: Oertli
authors.forename: Rohini
authors.initials: R
authors.lastname: Kuner
authors.forename: Dies
authors.initials: D
authors.lastname: Meijer
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollscheid
authors.forename: Axel
authors.initials: A
authors.lastname: Niemann
authors.forename: Ueli
authors.initials: U
authors.lastname: Suter
mesh_terms: D033962:Adaptor Protein Complex 2 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002966:Clathrin / Q000494:pharmacology*; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D034285:Dynamin II / Q000235:genetics*; D004622:Embryo, Mammalian; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D005434:Flow Cytometry; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D004676:Myelin Basic Protein / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D021381:Protein Transport / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014168:Transferrin / Q000378:metabolism
chemical_list: D033962:Adaptor Protein Complex 2; D002966:Clathrin; D016895:Culture Media, Serum-Free; D034285:Dynamin II; D049452:Green Fluorescent Proteins; D019012:Integrin beta1; D004676:Myelin Basic Protein; D016900:Neurofilament Proteins; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D014168:Transferrin; C485184:enhanced green fluorescent protein; C524056:Erbb2 protein, mouse