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Dysregulation in Subcellular Localization of Myelin Basic Protein mRNA Does Not Result in Altered Myelination in Amyotrophic Lateral Sclerosis

Barton, SK; Gregory, JM; Selvaraj, BT; McDade, K; Henstridge, CM; Spires-Jones, TL; James, OG; ... Chandran, S; + view all (2021) Dysregulation in Subcellular Localization of Myelin Basic Protein mRNA Does Not Result in Altered Myelination in Amyotrophic Lateral Sclerosis. Frontiers in Neuroscience , 15 , Article 705306. 10.3389/fnins.2021.705306. Green open access

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Abstract

Pathological hallmarks of amyotrophic lateral sclerosis (ALS), including protein misfolding, are well established in oligodendrocytes. More recently, an RNA trafficking deficit of key myelin proteins has been suggested in oligodendrocytes in ALS but the extent to which this affects myelination and the relative contribution of this to disease pathogenesis is unclear. ALS autopsy research findings showing demyelination contrasts with the routine clinical-pathological workup of ALS cases where it is rare to see white matter abnormalities other than simple Wallerian degeneration secondary to widespread neuronal loss. To begin to address this apparent variance, we undertook a comprehensive evaluation of myelination at an RNA, protein and structural level using human pathological material from sporadic ALS patients, genetic ALS patients (harboring C9orf72 mutation) and age- and sex-matched non-neurological controls. We performed (i) quantitative spatial profiling of the mRNA transcript encoding myelin basic protein (MBP), (ii) quantification of MBP protein and (iii) the first quantitative structural assessment of myelination in ALS post-mortem specimens by electron microscopy. We show no differences in MBP protein levels or ultrastructural myelination, despite a significant dysregulation in the subcellular trafficking of MBP mRNA in ALS patients compared to controls. We therefore confirm that whilst there are cell autonomous mRNA trafficking deficits affecting oligodendrocytes in ALS, this has no effect on myelin structure.

Type: Article
Title: Dysregulation in Subcellular Localization of Myelin Basic Protein mRNA Does Not Result in Altered Myelination in Amyotrophic Lateral Sclerosis
Open access status: An open access version is available from UCL Discovery
DOI: 10.3389/fnins.2021.705306
Publisher version: https://doi.org/10.3389/fnins.2021.705306
Language: English
Additional information: Copyright © 2021 Barton, Gregory, Selvaraj, McDade, Henstridge, Spires-Jones, James, Mehta, Story, Burr, Magnani, Isaacs, Smith and Chandran. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (http://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Keywords: oligodendrocytes, RNA trafficking, myelination, ALS, myelin basic protein
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10135888
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