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.
journal_name
Ann Clin Transl Neuroljournal_title
Annals of clinical and translational neurologyauthors
Klok MD,Bugiani M,de Vries SI,Gerritsen W,Breur M,van der Sluis S,Heine VM,Kole MHP,Baron W,van der Knaap MSdoi
10.1002/acn3.540subject
Has Abstractpub_date
2018-03-01 00:00:00pages
429-444issue
4issn
2328-9503pii
ACN3540journal_volume
5pub_type
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journal_title:Annals of clinical and translational neurology
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更新日期:2020-05-01 00:00:00
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pub_type: 杂志文章
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更新日期:2015-08-01 00:00:00
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更新日期:2015-11-06 00:00:00
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pub_type: 杂志文章
doi:10.1002/acn3.666
更新日期:2018-10-31 00:00:00
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pub_type: 杂志文章
doi:10.1002/acn3.267
更新日期:2015-12-08 00:00:00
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
doi:10.1002/acn3.50959
更新日期:2020-01-01 00:00:00
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pub_type: 杂志文章
doi:10.1002/acn3.50912
更新日期:2019-11-01 00:00:00
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pub_type: 杂志文章
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更新日期:2017-11-24 00:00:00
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更新日期:2016-08-14 00:00:00
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章,随机对照试验
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更新日期:2018-11-10 00:00:00
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
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更新日期:2020-12-28 00:00:00
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journal_title:Annals of clinical and translational neurology
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更新日期:2020-03-01 00:00:00
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pub_type: 杂志文章
doi:10.1002/acn3.203
更新日期:2015-06-01 00:00:00
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
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更新日期:2018-01-09 00:00:00
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更新日期:2018-04-02 00:00:00
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更新日期:2017-01-20 00:00:00
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
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更新日期:2017-05-17 00:00:00