Calcium channel agonists protect against neuromuscular dysfunction in a genetic model of TDP-43 mutation in ALS.
TAR DNA binding protein (TDP-43, encoded by the TARDBP gene) has recently been shown to be associated with amyotrophic lateral sclerosis (ALS), but the early pathophysiological deficits causing impairment in motor function are unknown. Here we expressed the wild-type human gene (wtTARDBP) or the ALS mutation G348C (mutTARDBP) in zebrafish larvae and characterized their motor (swimming) activity and the structure and function of their neuromuscular junctions (NMJs). Of these groups only mutTARDBP larvae showed impaired swimming and increased motoneuron vulnerability with reduced synaptic fidelity, reduced quantal transmission, and more orphaned presynaptic and postsynaptic structures at the NMJ. Remarkably, all behavioral and cellular features were stabilized by chronic treatment with either of the L-type calcium channel agonists FPL 64176 or Bay K 8644. These results indicate that expression of mutTARDBP results in defective NMJs and that calcium channel agonists could be novel therapeutics for ALS.
Department of Pathology and Cell Biology and Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montréal, QC, H3C 3J7, Canada. gary.ab.armstrong@gmail.com
Gary A B
GA
Armstrong
Pierre
P
Drapeau
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D009043:Motor Activity / Q000502:physiology; D009154:Mutation; D009469:Neuromuscular Junction / Q000187:drug effects / Q000473:pathology*; D018408:Patch-Clamp Techniques; D015027:Zebrafish
D002120:Calcium Channel Agonists; D004268:DNA-Binding Proteins