Amyotrophic lateral sclerosis (ALS) is characterised by progressive motor neuron degeneration. Although there areover 40 genes associated with causal monogenetic mutations, the majority of ALS patients are not geneticallydetermined. Causal ALS mutations are being increasingly mechanistically studied, though how these mechanismsconverge 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 isimplicated in selective motor neuron death is enhanced-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate(AMPAR)-mediated excitoxicity. Specifically, humanin vitroand pathological evidence has linked theC9orf72repeat expansion mutation to a relative increase in the Ca2+-permeable AMPAR population due to AMPAR subunitdysregulation. Here, we provide the first comparative quantitative assessment of the expression profile of AMPARsubunit transcripts, using BaseScope, in post-mortem lower motor neurons (spinal cord, anterior horn), uppermotor neurons (motor cortex) and neurons of the pre-frontal cortex in sALS and fALS due to mutations inSOD1andC9orf72. Our data indicated that AMPAR dysregulation is prominent in lower motor neurons in all ALS cases.However, sALS and mutantC9orf72cases exhibitedGluA1upregulation whereas mutant SOD1 cases displayedGluA2down regulation. We also showed that sALS cases exhibited widespread AMPAR dysregulation in the motorand pre-frontal cortex, though the exact identity of the AMPAR subunit being dysregulated was dependent on brainregion. In contrast, AMPAR dysregulation in mutantSOD1andC9orf72cases was restricted to lower motor neuronsonly. Our data highlight the complex dysregulation of AMPAR subunit expression that reflects both convergingand diverging mechanisms at play between different brain regions and between ALS cohorts.
Bibliographical noteAcknowledgementsThe authors would like to thank: (i) the MRC EdinburghBrain Bank for supplying all post-mortem brain materialand the Scottish MND register for all clinical and demo-graphic data as well people with ALS and their familiesfor making this research possible by making these gen-erous tissue donations; (ii) The Scottish MND ClinicalSpecialist team in discussing and obtaining consent fromMND patients for inclusion in these resources; and (iii)MND Scotland and the Sylvia Aitken Charitable Trustfor funding to CS to help to establish the MND Tissuebank. JMG is funded by a starter grant for clinical lec-turers from the Academy of Medical Sciences (210JMG3102 R45620) and brain bank funding is from the MRC(MR/L016400/1).
Academy of Medical Sciences. Grant Number: 210JMG 3102 R45620
Medical Research Council. Grant Number: MR/L016400/1