Journal
JOURNAL OF COMPARATIVE NEUROLOGY
Volume 524, Issue 7, Pages 1424-1442Publisher
WILEY
DOI: 10.1002/cne.23917
Keywords
extraocular; tongue; lumbricals; oculomotor; SOD1; SMN
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Funding
- EU Joint Programme for Neurodegenerative Disease (JPND)
- Ragnar Soderbergs Stiftelse [M245/11]
- Swedish Medical Research Council (Vetenskapsradet) [2011-2651]
- Birgit Backmark Donation
- Stiftelsen Olle Engkvist Byggmastare [2014/204]
- Karolinska Institutet Fonder
- Ahlen-stiftelsen [mB8/h11, mB8/h12, mB8/h13, mB8/14]
- Prinses Beatrix Spierfonds [W.S14-06]
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Neuromuscular junctions are primary pathological targets in the lethal motor neuron diseases spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). Synaptic pathology and denervation of target muscle fibers has been reported prior to the appearance of clinical symptoms in mouse models of both diseases, suggesting that neuromuscular junctions are highly vulnerable from the very early stages, and are a key target for therapeutic intervention. Here we examined neuromuscular pathology longitudinally in three clinically relevant muscle groups in mouse models of ALS and SMA in order to assess their relative vulnerabilities. We show for the first time that neuromuscular junctions of the extraocular muscles (responsible for the control of eye movement) were resistant to degeneration in endstage SMA mice, as well as in late symptomatic ALS mice. Tongue muscle neuromuscular junctions were also spared in both animal models. Conversely, neuromuscular junctions of the lumbrical muscles of the hind-paw were vulnerable in both SMA and ALS, with a loss of neuronal innervation and shrinkage of motor endplates in both diseases. Thus, the pattern of selective vulnerability was conserved across these two models of motor neuron disease. However, the first evidence of neuromuscular pathology occurred at different timepoints of disease progression, with much earlier evidence of presynaptic involvement in ALS, progressing to changes on the postsynaptic side. Conversely, in SMA changes appeared concomitantly at the neuromuscular junction, suggesting that mechanisms of neuromuscular disruption are distinct in these diseases. (c) 2015 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.
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