Dynamin 2 mutations in Charcot-Marie-Tooth neuropathy highlight the importance of clathrin-mediated endocytosis in myelination

Páris N M Sidiropoulos, Michaela Miehe, Thomas Bock, Elisa Tinelli, Carole I Oertli, Rohini Kuner, Dies Meijer, Bernd Wollscheid, Axel Niemann, Ueli Suter

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1395-411
Number of pages17
JournalBrain
Volume135
Issue numberPt 5
DOIs
Publication statusPublished - May 2012

Keywords

  • Adaptor Protein Complex 2
  • Animals
  • Antigens, CD29
  • Cell Differentiation
  • Cells, Cultured
  • Clathrin
  • Culture Media, Serum-Free
  • Dynamin II
  • Embryo, Mammalian
  • Endocytosis
  • Flow Cytometry
  • Ganglia, Spinal
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Green Fluorescent Proteins
  • Humans
  • Mice
  • Mice, Transgenic
  • Mutation
  • Myelin Basic Protein
  • Neurofilament Proteins
  • Neurons
  • Protein Transport
  • RNA, Small Interfering
  • Rats
  • Receptor, ErbB-2
  • Schwann Cells
  • Time Factors
  • Transfection
  • Transferrin

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