Dynamin 2 mutations in Charcot-Marie-Tooth neuropathy highlight the importance of clathrin-mediated endocytosis in myelination.
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.
Institute of Molecular Health Sciences, Chair in Cell Biology, ETH Zurich, ETH-Hönggerberg, Schafmattstrasse 18, Zurich, Switzerland.
SourceBrain : a journal of neurology 135:Pt 5 2012 May pg 1395-411
MeSHAdaptor Protein Complex 2
Culture Media, Serum-Free
Gene Expression Regulation
Gene Knockdown Techniques
Green Fluorescent Proteins
Myelin Basic Proteins
RNA, Small Interfering
Pub Type(s)Journal Article
Research Support, Non-U.S. Gov't