Dynamin 2 mutations in Charcot-Marie-Tooth neuropathy highlight the importance of clathrin-mediated endocytosis in myelination
| Autor: | Ueli Suter, Thomas Bock, Páris N. M. Sidiropoulos, Axel Niemann, Dies Meijer, Michaela Miehe, Rohini Kuner, Carole I. Oertli, Elisa Tinelli, Bernd Wollscheid |
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| Přispěvatelé: | Molecular Genetics |
| Rok vydání: | 2012 |
| Předmět: |
Time Factors
Receptor ErbB-2 Dynamin II Culture Media Serum-Free Mice 0302 clinical medicine Neurofilament Proteins Ganglia Spinal RNA Small Interfering Cells Cultured Genetics Neurons 0303 health sciences Integrin beta1 Transferrin Cell Differentiation Flow Cytometry Endocytosis 3. Good health Cell biology Protein Transport Gene Knockdown Techniques Hereditary motor and sensory neuropathy Green Fluorescent Proteins Adaptor Protein Complex 2 Mice Transgenic Biology Transfection 03 medical and health sciences medicine Animals Humans Autosomal dominant centronuclear myopathy 030304 developmental biology Dynamin Myelin Basic Protein Receptor-mediated endocytosis medicine.disease Embryo Mammalian Clathrin Myelin basic protein Rats DNM2 Gene Expression Regulation Mutation biology.protein Charcot-Marie-Tooth disease Myelination Dynamin 2 Neurology (clinical) Schwann Cells 030217 neurology & neurosurgery |
| Zdroj: | Brain : a journal of neurology Brain, 135, 1395-1411. Oxford University Press Brain: A Journal of Neurology, 135 (5) |
| ISSN: | 1460-2156 0006-8950 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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