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.
| Original language | English |
|---|---|
| Article number | 705306 |
| Number of pages | 10 |
| Journal | Frontiers in Neuroscience |
| Volume | 15 |
| DOIs | |
| Publication status | Published - 21 Sept 2021 |
Bibliographical note
The authors would like to thank: (i) the MRC Edinburgh Brain Bank for supplying all post-mortem brain material; (ii) The Scottish MND Clinical Specialist team for discussing and obtaining consent from MND patients for inclusion in these resources; (iii) MND Scotland and the Sylvia Aitken Charitable Trust for funding to CS to help to establish the MND Tissue bank. Work has been funded by the Australian National Health and Medical Research Council and the Australian Research Council (NHMRC-ARC; APP1110040), Medical Research Council (MRC UK; MR/L016400/1), Academy of Medical Sciences (AMS; 210JMG 3102 R45620), Euan MacDonald Centre, MND Scotland, UK Dementia Research Institute, which receives its funding from DRI Ltd., funded by the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK, the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 681181 and Royal Society of Edinburgh (CRF). ARM is a Lady Edith Wolfson Clinical Fellow and is jointly funded by the Medical Research Council (MRC) and the Motor Neurone Disease Association (MR/R001162/1). BTS is a Rowling-DRI fellow – administered by the Anne Rowling Regenerative Neurology Clinic (ARRNC), University of Edinburgh.Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Keywords
- oligodendrocytes
- RNA trafficking
- myelination
- ALS
- myelin basic protein
Access to Document
- Barton_etal_FN_Dysregulation_in_Subcellular_VOR
Copyright © 2021 Barton, Gregory, Selvaraj, McDade, Henstridge, Spires-Jones, James, Mehta, Story, Burr, Magnani, Isaacs, Smith and Chandran. This is an openaccess article distributed under the terms of the Creative Commons Attribution License (CC BY). 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 https://creativecommons.org/licenses/by/4.0/