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.

Links

Publisher Full Text

Authors

Sidiropoulos PN, Miehe M, Bock T, Tinelli E, Oertli CI, Kuner R, Meijer D, Wollscheid B, Niemann A, Suter U

Institution

Institute of Molecular Health Sciences, Chair in Cell Biology, ETH Zurich, ETH-Hönggerberg, Schafmattstrasse 18, Zurich, Switzerland.

Source

Brain : a journal of neurology 135:Pt 5 2012 May pg 1395-411

MeSH

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 Proteins
Neurofilament Proteins
Neurons
Protein Transport
RNA, Small Interfering
Rats
Receptor, erbB-2
Schwann Cells
Time Factors
Transfection
Transferrin

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22451505