|ZFIN ID: ZDB-PUB-170505-3|
Augmented quantal release of acetylcholine at the vertebrate neuromuscular junction following tdp-43 depletion
Dzieciolowska, S., Drapeau, P., Armstrong, G.A.B.
|Source:||PLoS One 12: e0177005 (Journal)|
|Registered Authors:||Drapeau, Pierre|
|Keywords:||Larvae, Zebrafish, Biological locomotion, Swimming, Motor neurons, Embryos, Muscle cells, Neuromuscular junctions|
|PubMed:||28472174 Full text @ PLoS One|
Dzieciolowska, S., Drapeau, P., Armstrong, G.A.B. (2017) Augmented quantal release of acetylcholine at the vertebrate neuromuscular junction following tdp-43 depletion. PLoS One. 12:e0177005.
ABSTRACTTAR DNA binding protein (TDP-43) is a 43 kD, predominately nuclear, protein involved in RNA metabolism. Of clinical significance is that the majority of amyotrophic lateral sclerosis (ALS) patients display abnormal accumulation of misfolded TDP-43 in the cytoplasm, which is coincident with a loss of nuclear localization in the afflicted regions of the central nervous system. Little is known about defects that arise in loss-of-function models, in particular synaptic defects that arise at the neuromuscular junction (NMJ). In this report, we examined abnormalities arising at the NMJ following depletion of tdp-43 using a previously characterized mutant tardbp (encoding tdp-43) zebrafish line containing a premature stop codon (Y220X) that results in an unstable and degraded protein. Homozygous tardbpY220X/Y220X zebrafish do not produce tdp-43 but develop normally due to expression of an alternative splice variant of tardbpl (tardbp paralog). Using an antisense morpholino oligonucleotide to knockdown expression of the tardbpl in tardbpY220X/Y220X embryos, we examined locomotor defects, NMJ structural abnormalities and release of quantal synaptic vesicles at the NMJ. As in previous reports, larvae depleted of tdp-43 display reduced survival, gross morphological defects and severely impaired locomotor activity. These larvae also displayed an increased number of orphaned pre- and postsynaptic NMJ markers but surprisingly, we observed a significant increase (3.5 times) in the frequency of quantal acetylcholine release at the NMJ in larvae depleted of tdp-43. These results indicate that reduced TDP-43 levels alter quantal vesicle release at the NMJ during vertebrate development and may be relevant for understanding synaptic dysfunction in ALS.