Cross-disease comparison of amyotrophic lateral sclerosis and spinal muscular atrophy reveals conservation of selective vulnerability but differential neuromuscular junction pathology.
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. J. Comp. Neurol. 524:1424-1442, 2016. © 2015 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Laura H
LH
Comley
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Jik
J
Nijssen
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Johanna
J
Frost-Nylen
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Eva
E
Hedlund
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology*; D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D021621:Imaging, Three-Dimensional; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009469:Neuromuscular Junction / Q000473:pathology*; D061848:Optical Imaging; D013482:Superoxide Dismutase / Q000235:genetics; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics / Q000378:metabolism
D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C000597152:SMN2 protein, mouse; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; C489614:Sv2a protein, mouse; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase
SMN; SOD1; extraocular; lumbricals; oculomotor; tongue