Augmented quantal release of acetylcholine at the vertebrate neuromuscular junction following tdp-43 depletionReportar como inadecuado




Augmented quantal release of acetylcholine at the vertebrate neuromuscular junction following tdp-43 depletion - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

TAR 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.



Autor: Stefania Dzieciolowska, Pierre Drapeau, Gary Alan Barclay Armstrong

Fuente: http://plos.srce.hr/



DESCARGAR PDF




Documentos relacionados