Abstract
Amyotrophic lateral sclerosis (ALS) is characterised by progressive motor neuron degeneration. Although there are over 40 genes associated with causal monogenetic mutations, the majority of ALS patients are not genetically determined. Causal ALS mutations are being increasingly mechanistically studied, though how these mechanisms converge and diverge between the multiple known familial causes of ALS (fALS) and sporadic forms of ALS (sALS) and furthermore between different neuron types, is poorly understood. One common pathway that is implicated in selective motor neuron death is enhanced α‐amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazole‐propionate (AMPAR)‐mediated excitoxicity. Specifically, human in vitro and pathological evidence has linked the C9orf72 repeat expansion mutation to a relative increase in the Ca2+‐permeable AMPAR population due to AMPAR subunit dysregulation. Here, we provide the first comparative quantitative assessment of the expression profile of AMPAR subunit transcripts, using BaseScope, in post‐mortem lower motor neurons (spinal cord, anterior horn), upper motor neurons (motor cortex) and neurons of the pre‐frontal cortex in sALS and fALS due to mutations in SOD1 and C9orf72. Our data indicated that AMPAR dysregulation is prominent in lower motor neurons in all ALS cases. However, sALS and mutant C9orf72 cases exhibited GluA1 upregulation whereas mutant SOD1 cases displayed GluA2 down regulation. We also showed that sALS cases exhibited widespread AMPAR dysregulation in the motor and pre‐frontal cortex, though the exact identity of the AMPAR subunit being dysregulated was dependent on brain region. In contrast, AMPAR dysregulation in mutant SOD1 and C9orf72 cases was restricted to lower motor neurons only. Our data highlight the complex dysregulation of AMPAR subunit expression that reflects both converging and diverging mechanisms at play between different brain regions and between ALS cohorts. © 2019 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Highlights
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and invariably fatal neurodegenerative disease characterised by degeneration of motor neurons of the brain and spinal cord
To determine whether amino-3-hydroxyl-5-methyl4-isoxazole-propionate receptors (AMPARs) subunit dysregulation is associated with upper and lower motor neurons or, non-motor neurons in other brain regions affected by TDP-43 pathology in ALS patients we examined AMPAR subunit expression in the post-mortem prefrontal cortex (BA9) of sporadic ALS (sALS), C9orf72RE and SOD1 I114T patients (Figure 5A)
We examined how the shift in GluA2/GluATOTAL ratio in sALS prefrontal cortex with respect to control was underpinned by regulation of individual AMPAR subunits by normalisation of each subunit data to GluA2 for each patient (Figure 6D)
Summary
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and invariably fatal neurodegenerative disease characterised by degeneration of motor neurons of the brain and spinal cord. Only a small proportion of total ALS cases (5–10%) are linked to hereditary mutations and the proportion of apparently sporadic ALS (sALS) cases having a genetic basis remains ∼10% [1,2]. In this regard, modelling sALS has been challenging and the majority of ALS research has been conducted on models based on genetic mutations including the C9orf repeat expansion (C9orf72RE) mutation and mutations to SOD1, which represent the two most frequent known familial and sporadic ALS mutations [1,2]. The extrapolation and relevance of how these pathways converge and diverge between the multiple known familial causes of ALS and sporadic forms of ALS is largely unknown
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