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C9ORF72-related cellular pathology in skeletal myocytes derived from ALS-patient induced pluripotent stem cells

Amyotrophic lateral sclerosis (ALS) is a late-onset neuromuscular disease with no cure and limited treatment options. Patients experience a gradual paralysis leading to death from respiratory complications on average only 2-5 years after diagnosis. There is increasing evidence that skeletal muscle i...

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Autores principales: Lynch, Eileen, Semrad, Theran, Belsito, Vincent S., FitzGibbons, Claire, Reilly, Megan, Hayakawa, Koji, Suzuki, Masatoshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737948/
https://www.ncbi.nlm.nih.gov/pubmed/31439573
http://dx.doi.org/10.1242/dmm.039552
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author Lynch, Eileen
Semrad, Theran
Belsito, Vincent S.
FitzGibbons, Claire
Reilly, Megan
Hayakawa, Koji
Suzuki, Masatoshi
author_facet Lynch, Eileen
Semrad, Theran
Belsito, Vincent S.
FitzGibbons, Claire
Reilly, Megan
Hayakawa, Koji
Suzuki, Masatoshi
author_sort Lynch, Eileen
collection PubMed
description Amyotrophic lateral sclerosis (ALS) is a late-onset neuromuscular disease with no cure and limited treatment options. Patients experience a gradual paralysis leading to death from respiratory complications on average only 2-5 years after diagnosis. There is increasing evidence that skeletal muscle is affected early in the disease process, yet the pathological processes occurring in the skeletal muscle of ALS patients are still mostly unknown. Specifically, the most common genetic cause of ALS, a hexanucleotide repeat expansion in the C9ORF72 gene, has yet to be fully characterized in the context of skeletal muscle. In this study, we used the protocol previously developed in our lab to differentiate skeletal myocytes from induced pluripotent stem cells (iPSCs) of C9ORF72 ALS (C9-ALS) patients in order to create an in vitro disease model of C9-ALS skeletal muscle pathology. Of the three C9ORF72 mutation hallmarks, we did not see any evidence of haploinsufficiency, but we did detect RNA foci and dipeptide repeat (DPR) proteins. Additional abnormalities included changes in the expression of mitochondrial genes and a susceptibility to oxidative stress, indicating that mitochondrial dysfunction may be a critical feature of C9-ALS skeletal muscle pathology. Finally, the C9-ALS myocytes had increased expression and aggregation of TDP-43. Together, these data show that skeletal muscle cells experience pathological changes due to the C9ORF72 mutation. Our in vitro model could facilitate further study of cellular and molecular pathology in ALS skeletal muscle in order to discover new therapeutic targets against this devastating disease. This article has an associated First Person interview with the first author of the paper.
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spelling pubmed-67379482019-09-12 C9ORF72-related cellular pathology in skeletal myocytes derived from ALS-patient induced pluripotent stem cells Lynch, Eileen Semrad, Theran Belsito, Vincent S. FitzGibbons, Claire Reilly, Megan Hayakawa, Koji Suzuki, Masatoshi Dis Model Mech Research Article Amyotrophic lateral sclerosis (ALS) is a late-onset neuromuscular disease with no cure and limited treatment options. Patients experience a gradual paralysis leading to death from respiratory complications on average only 2-5 years after diagnosis. There is increasing evidence that skeletal muscle is affected early in the disease process, yet the pathological processes occurring in the skeletal muscle of ALS patients are still mostly unknown. Specifically, the most common genetic cause of ALS, a hexanucleotide repeat expansion in the C9ORF72 gene, has yet to be fully characterized in the context of skeletal muscle. In this study, we used the protocol previously developed in our lab to differentiate skeletal myocytes from induced pluripotent stem cells (iPSCs) of C9ORF72 ALS (C9-ALS) patients in order to create an in vitro disease model of C9-ALS skeletal muscle pathology. Of the three C9ORF72 mutation hallmarks, we did not see any evidence of haploinsufficiency, but we did detect RNA foci and dipeptide repeat (DPR) proteins. Additional abnormalities included changes in the expression of mitochondrial genes and a susceptibility to oxidative stress, indicating that mitochondrial dysfunction may be a critical feature of C9-ALS skeletal muscle pathology. Finally, the C9-ALS myocytes had increased expression and aggregation of TDP-43. Together, these data show that skeletal muscle cells experience pathological changes due to the C9ORF72 mutation. Our in vitro model could facilitate further study of cellular and molecular pathology in ALS skeletal muscle in order to discover new therapeutic targets against this devastating disease. This article has an associated First Person interview with the first author of the paper. The Company of Biologists Ltd 2019-08-01 2019-08-16 /pmc/articles/PMC6737948/ /pubmed/31439573 http://dx.doi.org/10.1242/dmm.039552 Text en © 2019. 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
Lynch, Eileen
Semrad, Theran
Belsito, Vincent S.
FitzGibbons, Claire
Reilly, Megan
Hayakawa, Koji
Suzuki, Masatoshi
C9ORF72-related cellular pathology in skeletal myocytes derived from ALS-patient induced pluripotent stem cells
title C9ORF72-related cellular pathology in skeletal myocytes derived from ALS-patient induced pluripotent stem cells
title_full C9ORF72-related cellular pathology in skeletal myocytes derived from ALS-patient induced pluripotent stem cells
title_fullStr C9ORF72-related cellular pathology in skeletal myocytes derived from ALS-patient induced pluripotent stem cells
title_full_unstemmed C9ORF72-related cellular pathology in skeletal myocytes derived from ALS-patient induced pluripotent stem cells
title_short C9ORF72-related cellular pathology in skeletal myocytes derived from ALS-patient induced pluripotent stem cells
title_sort c9orf72-related cellular pathology in skeletal myocytes derived from als-patient induced pluripotent stem cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737948/
https://www.ncbi.nlm.nih.gov/pubmed/31439573
http://dx.doi.org/10.1242/dmm.039552
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