Axonal abnormalities in vanishing white matter
| Autor: | Klok, Melanie D, Bugiani, Marianna, de Vries, Sharon I, Gerritsen, Wouter, Breur, Marjolein, van der Sluis, Sophie, Heine, Vivi M, Kole, Maarten H P, Baron, Wia, van der Knaap, Marjo S, Sub Cell Biology, Celbiologie |
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| Přispěvatelé: | Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Functional Genomics, Netherlands Institute for Neuroscience (NIN), Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Pediatric surgery, Pathology, VU University medical center, Human genetics, Amsterdam Reproduction & Development (AR&D), Molecular Neuroscience and Ageing Research (MOLAR), Sub Cell Biology, Celbiologie |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pathology medicine.medical_specialty NERVOUS-SYSTEM HYPOMYELINATION LEUKOENCEPHALOPATHY Corpus callosum ASTROCYTES DISEASE MATURATION White matter Leukoencephalopathy 03 medical and health sciences Myelin 0302 clinical medicine Atrophy Medicine Research Articles business.industry General Neuroscience IN-VITRO medicine.disease Spinal cord 030104 developmental biology medicine.anatomical_structure nervous system INITIATION-FACTOR EIF2B Forebrain Axoplasmic transport Neurology (clinical) CHILDHOOD ATAXIA SPINAL-CORD MYELINATION business 030217 neurology & neurosurgery Research Article |
| Zdroj: | Annals of Clinical and Translational Neurology, 5(4), 429-444. John Wiley and Sons Ltd Klok, M D, Bugiani, M, de Vries, S I, Gerritsen, W, Breur, M, van der Sluis, S, Heine, V M, Kole, M H P, Baron, W & van der Knaap, M S 2018, ' Axonal abnormalities in vanishing white matter ', Annals of Clinical and Translational Neurology, vol. 5, no. 4, pp. 429-444 . https://doi.org/10.1002/acn3.540 Annals of Clinical and Translational Neurology Annals of Clinical and Translational Neurology, 5(4), 429. John Wiley and Sons Ltd Annals of Clinical and Translational Neurology, 5, 429-444. John Wiley and Sons Ltd Annals of Clinical and Translational Neurology, 5(4), 429-444. Wiley |
| ISSN: | 2328-9503 |
| DOI: | 10.1002/acn3.540 |
| Popis: | ObjectiveWe aimed to study the occurrence and development of axonal pathology and the influence of astrocytes in vanishing white matter.MethodsAxons and myelin were analyzed using electron microscopy and immunohistochemistry on Eif2b4 and Eif2b5 single- and double-mutant mice and patient brain tissue. In addition, astrocyte-forebrain co-culture studies were performed.ResultsIn the corpus callosum of Eif2b5-mutant mice, myelin sheath thickness, axonal diameter, and G-ratio developed normally up to 4 months. At 7 months, however, axons had become thinner, while in control mice axonal diameters had increased further. Myelin sheath thickness remained close to normal, resulting in an abnormally low G-ratio in Eif2b5-mutant mice. In more severely affected Eif2b4-Eif2b5 double-mutants, similar abnormalities were already present at 4 months, while in milder affected Eif2b4 mutants, few abnormalities were observed at 7 months. Additionally, from 2 months onward an increased percentage of thin, unmyelinated axons and increased axonal density were present in Eif2b5-mutant mice. Co-cultures showed that Eif2b5 mutant astrocytes induced increased axonal density, also in control forebrain tissue, and that control astrocytes induced normal axonal density, also in mutant forebrain tissue. In vanishing white matter patient brains, axons and myelin sheaths were thinner than normal in moderately and severely affected white matter. In mutant mice and patients, signs of axonal transport defects and cytoskeletal abnormalities were minimal.InterpretationIn vanishing white matter, axons are initially normal and atrophy later. Astrocytes are central in this process. If therapy becomes available, axonal pathology may be prevented with early intervention. |
| Databáze: | OpenAIRE |
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