Axonal abnormalities in vanishing white matter

Melanie D. Klok, Marianna Bugiani, Sharon I. de Vries, Wouter Gerritsen, Marjolein Breur, Sophie van der Sluis, Vivi M. Heine, Maarten H.P. Kole, Wia Baron, Marjo S. van der Knaap

Research output: Contribution to JournalArticleAcademicpeer-review

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 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.

Original languageEnglish
Pages (from-to)429-444
Number of pages16
JournalAnnals of Clinical and Translational Neurology
Volume5
Issue number4
DOIs
Publication statusPublished - 1 Apr 2018

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Astrocytes
Axons
Myelin Sheath
Prosencephalon
Coculture Techniques
Pathology
Axonal Transport
Corpus Callosum
Brain
Atrophy
White Matter
Electron Microscopy
Immunohistochemistry
Therapeutics

Cite this

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. / Axonal abnormalities in vanishing white matter. In: Annals of Clinical and Translational Neurology. 2018 ; Vol. 5, No. 4. pp. 429-444.
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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 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.",
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Klok, MD, Bugiani, M, de Vries, SI, Gerritsen, W, Breur, M, van der Sluis, S, Heine, VM, Kole, MHP, Baron, W & van der Knaap, MS 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

Axonal abnormalities in vanishing white matter. / 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.

In: Annals of Clinical and Translational Neurology, Vol. 5, No. 4, 01.04.2018, p. 429-444.

Research output: Contribution to JournalArticleAcademicpeer-review

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AU - Klok, Melanie D.

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AU - de Vries, Sharon I.

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AU - Heine, Vivi M.

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