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.
Highlights
Oligodendrocyte pathology has been demonstrated in amyotrophic lateral sclerosis (ALS) postmortem tissue (Kang et al, 2013; Philips et al, 2013; Lorente Pons et al, 2020); the relevance and/or contribution of this pathology to disease pathogenesis is relatively understudied
Quantification showed an increased number of oligodendrocytes with seven or more myelin basic protein (MBP) mRNA transcripts in C9orf72 ALS patients compared to controls (p = 0.043; Figure 1D) as well as an overall increase in the number of oligodendrocytes with aggregations of MBP mRNAs compared to controls (p = 0.013)
To determine if the RNA trafficking deficit was specific to MBP or affected other oligodendrocyte-specific mRNAs not involved in myelin production as previously reported (Lorente Pons et al, 2020) we examined the distribution of carbonic anhydrase II (CAII)
Summary
Oligodendrocyte pathology has been demonstrated in ALS postmortem tissue (Kang et al, 2013; Philips et al, 2013; Lorente Pons et al, 2020); the relevance and/or contribution of this pathology to disease pathogenesis is relatively understudied. Disrupted RNA trafficking and metabolism has been demonstrated in neurons in ALS and the relevance of these findings to oligodendrocytes, which display the hallmark pathologies of ALS as well as rely on local translation of many RNAs involved in myelination and metabolism, is becoming clearer through the examination of post-mortem patient samples (Khalil et al, 2018; Lorente Pons et al, 2020). We have shown previously that up to a fifth of ALS cases (sporadic and genetic) examined at postmortem have a purely glial pathological signature, with little if any neuronal pathology in non-motor brain regions (Gregory et al, 2019)
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