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- Title
Axonal abnormalities in vanishing white matter.
- Authors
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.
- Abstract
Abstract: Objective: We aimed to study the occurrence and development of axonal pathology and the influence of astrocytes in vanishing white matter. Methods: Axons and myelin were analyzed using electron microscopy and immunohistochemistry on <italic>Eif2b4</italic> and <italic>Eif2b5</italic> single‐ and double‐mutant mice and patient brain tissue. In addition, astrocyte‐forebrain co‐culture studies were performed. Results: In the corpus callosum of <italic>Eif2b5‐</italic>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 <italic>Eif2b5‐</italic>mutant mice. In more severely affected <italic>Eif2b4‐Eif2b5</italic> double‐mutants, similar abnormalities were already present at 4 months, while in milder affected <italic>Eif2b4</italic> 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 <italic>Eif2b5</italic>‐mutant mice. Co‐cultures showed that <italic>Eif2b5</italic> 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. Interpretation: In 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.
- Subjects
AXONS; VANISHING white matter disease; ELECTRON microscopy; IMMUNOHISTOCHEMISTRY; ASTROCYTES; CELL culture; DISEASES
- Publication
Annals of Clinical & Translational Neurology, 2018, Vol 5, Issue 4, p429
- ISSN
2328-9503
- Publication type
Article
- DOI
10.1002/acn3.540