Cargando…

Role of BMP receptor traffic in synaptic growth defects in an ALS model

TAR DNA-binding protein 43 (TDP-43) is genetically and functionally linked to amyotrophic lateral sclerosis (ALS) and regulates transcription, splicing, and transport of thousands of RNA targets that function in diverse cellular pathways. In ALS, pathologically altered TDP-43 is believed to lead to...

Descripción completa

Detalles Bibliográficos
Autores principales: Deshpande, Mugdha, Feiger, Zachary, Shilton, Amanda K., Luo, Christina C., Silverman, Ethan, Rodal, Avital A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042577/
https://www.ncbi.nlm.nih.gov/pubmed/27535427
http://dx.doi.org/10.1091/mbc.E16-07-0519
_version_ 1782456618509664256
author Deshpande, Mugdha
Feiger, Zachary
Shilton, Amanda K.
Luo, Christina C.
Silverman, Ethan
Rodal, Avital A.
author_facet Deshpande, Mugdha
Feiger, Zachary
Shilton, Amanda K.
Luo, Christina C.
Silverman, Ethan
Rodal, Avital A.
author_sort Deshpande, Mugdha
collection PubMed
description TAR DNA-binding protein 43 (TDP-43) is genetically and functionally linked to amyotrophic lateral sclerosis (ALS) and regulates transcription, splicing, and transport of thousands of RNA targets that function in diverse cellular pathways. In ALS, pathologically altered TDP-43 is believed to lead to disease by toxic gain-of-function effects on RNA metabolism, as well as by sequestering endogenous TDP-43 and causing its loss of function. However, it is unclear which of the numerous cellular processes disrupted downstream of TDP-43 dysfunction lead to neurodegeneration. Here we found that both loss and gain of function of TDP-43 in Drosophila cause a reduction of synaptic growth–promoting bone morphogenic protein (BMP) signaling at the neuromuscular junction (NMJ). Further, we observed a shift of BMP receptors from early to recycling endosomes and increased mobility of BMP receptor–containing compartments at the NMJ. Inhibition of the recycling endosome GTPase Rab11 partially rescued TDP-43–induced defects in BMP receptor dynamics and distribution and suppressed BMP signaling, synaptic growth, and larval crawling defects. Our results indicate that defects in receptor traffic lead to neuronal dysfunction downstream of TDP-43 misregulation and that rerouting receptor traffic may be a viable strategy for rescuing neurological impairment.
format Online
Article
Text
id pubmed-5042577
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher The American Society for Cell Biology
record_format MEDLINE/PubMed
spelling pubmed-50425772016-12-16 Role of BMP receptor traffic in synaptic growth defects in an ALS model Deshpande, Mugdha Feiger, Zachary Shilton, Amanda K. Luo, Christina C. Silverman, Ethan Rodal, Avital A. Mol Biol Cell Articles TAR DNA-binding protein 43 (TDP-43) is genetically and functionally linked to amyotrophic lateral sclerosis (ALS) and regulates transcription, splicing, and transport of thousands of RNA targets that function in diverse cellular pathways. In ALS, pathologically altered TDP-43 is believed to lead to disease by toxic gain-of-function effects on RNA metabolism, as well as by sequestering endogenous TDP-43 and causing its loss of function. However, it is unclear which of the numerous cellular processes disrupted downstream of TDP-43 dysfunction lead to neurodegeneration. Here we found that both loss and gain of function of TDP-43 in Drosophila cause a reduction of synaptic growth–promoting bone morphogenic protein (BMP) signaling at the neuromuscular junction (NMJ). Further, we observed a shift of BMP receptors from early to recycling endosomes and increased mobility of BMP receptor–containing compartments at the NMJ. Inhibition of the recycling endosome GTPase Rab11 partially rescued TDP-43–induced defects in BMP receptor dynamics and distribution and suppressed BMP signaling, synaptic growth, and larval crawling defects. Our results indicate that defects in receptor traffic lead to neuronal dysfunction downstream of TDP-43 misregulation and that rerouting receptor traffic may be a viable strategy for rescuing neurological impairment. The American Society for Cell Biology 2016-10-01 /pmc/articles/PMC5042577/ /pubmed/27535427 http://dx.doi.org/10.1091/mbc.E16-07-0519 Text en © 2016 Deshpande, Feiger, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Deshpande, Mugdha
Feiger, Zachary
Shilton, Amanda K.
Luo, Christina C.
Silverman, Ethan
Rodal, Avital A.
Role of BMP receptor traffic in synaptic growth defects in an ALS model
title Role of BMP receptor traffic in synaptic growth defects in an ALS model
title_full Role of BMP receptor traffic in synaptic growth defects in an ALS model
title_fullStr Role of BMP receptor traffic in synaptic growth defects in an ALS model
title_full_unstemmed Role of BMP receptor traffic in synaptic growth defects in an ALS model
title_short Role of BMP receptor traffic in synaptic growth defects in an ALS model
title_sort role of bmp receptor traffic in synaptic growth defects in an als model
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042577/
https://www.ncbi.nlm.nih.gov/pubmed/27535427
http://dx.doi.org/10.1091/mbc.E16-07-0519
work_keys_str_mv AT deshpandemugdha roleofbmpreceptortrafficinsynapticgrowthdefectsinanalsmodel
AT feigerzachary roleofbmpreceptortrafficinsynapticgrowthdefectsinanalsmodel
AT shiltonamandak roleofbmpreceptortrafficinsynapticgrowthdefectsinanalsmodel
AT luochristinac roleofbmpreceptortrafficinsynapticgrowthdefectsinanalsmodel
AT silvermanethan roleofbmpreceptortrafficinsynapticgrowthdefectsinanalsmodel
AT rodalavitala roleofbmpreceptortrafficinsynapticgrowthdefectsinanalsmodel