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Overexpression of an ALS-associated FUS mutation in C. elegans disrupts NMJ morphology and leads to defective neuromuscular transmission

The amyotrophic lateral sclerosis (ALS) neurodegenerative disorder has been associated with multiple genetic lesions, including mutations in the gene for fused in sarcoma (FUS), a nuclear-localized RNA/DNA-binding protein. Neuronal expression of the pathological form of FUS proteins in Caenorhabditi...

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Autores principales: Markert, Sebastian M., Skoruppa, Michael, Yu, Bin, Mulcahy, Ben, Zhen, Mei, Gao, Shangbang, Sendtner, Michael, Stigloher, Christian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746668/
https://www.ncbi.nlm.nih.gov/pubmed/33148607
http://dx.doi.org/10.1242/bio.055129
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author Markert, Sebastian M.
Skoruppa, Michael
Yu, Bin
Mulcahy, Ben
Zhen, Mei
Gao, Shangbang
Sendtner, Michael
Stigloher, Christian
author_facet Markert, Sebastian M.
Skoruppa, Michael
Yu, Bin
Mulcahy, Ben
Zhen, Mei
Gao, Shangbang
Sendtner, Michael
Stigloher, Christian
author_sort Markert, Sebastian M.
collection PubMed
description The amyotrophic lateral sclerosis (ALS) neurodegenerative disorder has been associated with multiple genetic lesions, including mutations in the gene for fused in sarcoma (FUS), a nuclear-localized RNA/DNA-binding protein. Neuronal expression of the pathological form of FUS proteins in Caenorhabditis elegans results in mislocalization and aggregation of FUS in the cytoplasm, and leads to impairment of motility. However, the mechanisms by which the mutant FUS disrupts neuronal health and function remain unclear. Here we investigated the impact of ALS-associated FUS on motor neuron health using correlative light and electron microscopy, electron tomography, and electrophysiology. We show that ectopic expression of wild-type or ALS-associated human FUS impairs synaptic vesicle docking at neuromuscular junctions. ALS-associated FUS led to the emergence of a population of large, electron-dense, and filament-filled endosomes. Electrophysiological recording revealed reduced transmission from motor neurons to muscles. Together, these results suggest a pathological effect of ALS-causing FUS at synaptic structure and function organization. This article has an associated First Person interview with the first author of the paper.
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spelling pubmed-77466682020-12-18 Overexpression of an ALS-associated FUS mutation in C. elegans disrupts NMJ morphology and leads to defective neuromuscular transmission Markert, Sebastian M. Skoruppa, Michael Yu, Bin Mulcahy, Ben Zhen, Mei Gao, Shangbang Sendtner, Michael Stigloher, Christian Biol Open Research Article The amyotrophic lateral sclerosis (ALS) neurodegenerative disorder has been associated with multiple genetic lesions, including mutations in the gene for fused in sarcoma (FUS), a nuclear-localized RNA/DNA-binding protein. Neuronal expression of the pathological form of FUS proteins in Caenorhabditis elegans results in mislocalization and aggregation of FUS in the cytoplasm, and leads to impairment of motility. However, the mechanisms by which the mutant FUS disrupts neuronal health and function remain unclear. Here we investigated the impact of ALS-associated FUS on motor neuron health using correlative light and electron microscopy, electron tomography, and electrophysiology. We show that ectopic expression of wild-type or ALS-associated human FUS impairs synaptic vesicle docking at neuromuscular junctions. ALS-associated FUS led to the emergence of a population of large, electron-dense, and filament-filled endosomes. Electrophysiological recording revealed reduced transmission from motor neurons to muscles. Together, these results suggest a pathological effect of ALS-causing FUS at synaptic structure and function organization. This article has an associated First Person interview with the first author of the paper. The Company of Biologists Ltd 2020-12-07 /pmc/articles/PMC7746668/ /pubmed/33148607 http://dx.doi.org/10.1242/bio.055129 Text en © 2020. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/4.0This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Markert, Sebastian M.
Skoruppa, Michael
Yu, Bin
Mulcahy, Ben
Zhen, Mei
Gao, Shangbang
Sendtner, Michael
Stigloher, Christian
Overexpression of an ALS-associated FUS mutation in C. elegans disrupts NMJ morphology and leads to defective neuromuscular transmission
title Overexpression of an ALS-associated FUS mutation in C. elegans disrupts NMJ morphology and leads to defective neuromuscular transmission
title_full Overexpression of an ALS-associated FUS mutation in C. elegans disrupts NMJ morphology and leads to defective neuromuscular transmission
title_fullStr Overexpression of an ALS-associated FUS mutation in C. elegans disrupts NMJ morphology and leads to defective neuromuscular transmission
title_full_unstemmed Overexpression of an ALS-associated FUS mutation in C. elegans disrupts NMJ morphology and leads to defective neuromuscular transmission
title_short Overexpression of an ALS-associated FUS mutation in C. elegans disrupts NMJ morphology and leads to defective neuromuscular transmission
title_sort overexpression of an als-associated fus mutation in c. elegans disrupts nmj morphology and leads to defective neuromuscular transmission
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746668/
https://www.ncbi.nlm.nih.gov/pubmed/33148607
http://dx.doi.org/10.1242/bio.055129
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