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

Frontiers in Neuroscience

Karina McDade¹  Colin Smith¹  Christopher M. Henstridge²  Tara L. Spires-Jones²  Adrian M. Isaacs³  Arpan R. Mehta⁶  David Story⁶  Jenna M. Gregory⁶  Karen Burr⁶  Siddharthan Chandran⁶  Dario Magnani⁶  Samantha K. Barton⁶  Owen G. James⁶  Bhuvaneish T. Selvaraj⁶ 

[1] Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, United Kingdom;Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh, United Kingdom;Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom;Euan MacDonald Centre for MND Research, The University of Edinburgh, Edinburgh, United Kingdom;Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia;UK Dementia Research Institute at The University of Edinburgh, The University of Edinburgh, Edinburgh, United Kingdom;UK Dementia Research Institute at UCL, Faculty of Brain Sciences, University College London, London, United Kingdom;

关键词: oligodendrocytes;    RNA trafficking;    myelination;    ALS;    myelin basic protein;   

DOI  :  10.3389/fnins.2021.705306

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown