Axonal abnormalities in vanishing white matter.

Autor: Klok MD; Department of Pediatrics/Child Neurology Amsterdam Neuroscience VU University Medical Centre Amsterdam The Netherlands., Bugiani M; Department of Pathology Amsterdam Neuroscience VU University Medical Centre Amsterdam The Netherlands., de Vries SI; Department of Axonal Signaling Netherlands Institute for Neuroscience Amsterdam The Netherlands., Gerritsen W; Department of Pathology Amsterdam Neuroscience VU University Medical Centre Amsterdam The Netherlands., Breur M; Department of Pathology Amsterdam Neuroscience VU University Medical Centre Amsterdam The Netherlands., van der Sluis S; Department of Complex Trait Genetics Center for Neurogenomics and Cognitive Research Amsterdam Neuroscience VU University Medical Centre Amsterdam The Netherlands., Heine VM; Department of Pediatrics/Child Neurology Amsterdam Neuroscience VU University Medical Centre Amsterdam The Netherlands.; Department of Complex Trait Genetics Center for Neurogenomics and Cognitive Research Amsterdam Neuroscience VU University Medical Centre Amsterdam The Netherlands., Kole MHP; Department of Axonal Signaling Netherlands Institute for Neuroscience Amsterdam The Netherlands.; Cell Biology Faculty of Science Utrecht University Utrecht The Netherlands., Baron W; Department of Cell Biology University Medical Center Groningen University of Groningen Groningen The Netherlands., van der Knaap MS; Department of Pediatrics/Child Neurology Amsterdam Neuroscience VU University Medical Centre Amsterdam The Netherlands.; Department of Functional Genomics Center for Neurogenomics and Cognitive Research Amsterdam Neuroscience VU University Amsterdam The Netherlands.
Jazyk: angličtina
Zdroj: Annals of clinical and translational neurology [Ann Clin Transl Neurol] 2018 Mar 01; Vol. 5 (4), pp. 429-444. Date of Electronic Publication: 2018 Mar 01 (Print Publication: 2018).
DOI: 10.1002/acn3.540
Abstrakt: 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 Eif2b4 and Eif2b5 single- and double-mutant mice and patient brain tissue. In addition, astrocyte-forebrain co-culture studies were performed.
Results: In 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.
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.
Databáze: MEDLINE
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