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Transactive response DNA-binding protein-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model

Oligodendrocytes are implicated in amyotrophic lateral sclerosis pathogenesis and display transactive response DNA-binding protein-43 (TDP-43) pathological inclusions. To investigate the cell autonomous consequences of TDP-43 mutations on human oligodendrocytes, we generated oligodendrocytes from pa...

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Autores principales: Barton, Samantha K, Magnani, Dario, James, Owen G, Livesey, Matthew R, Selvaraj, Bhuvaneish T, James, Owain T, Perkins, Emma M, Gregory, Jenna M, Cleary, Elaine, Ausems, C Rosanne M, Carter, Roderick N Carter, Vasistha, Navneet A, Zhao, Chen, Burr, Karen, Story, David, Cardinali, Alessandra, Morton, Nicholas M, Hardingham, Giles E, Wyllie, David J A, Chandran, Siddharthan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8936427/
https://www.ncbi.nlm.nih.gov/pubmed/35350711
http://dx.doi.org/10.1093/braincomms/fcab255
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author Barton, Samantha K
Magnani, Dario
James, Owen G
Livesey, Matthew R
Selvaraj, Bhuvaneish T
James, Owain T
Perkins, Emma M
Gregory, Jenna M
Cleary, Elaine
Ausems, C Rosanne M
Carter, Roderick N Carter
Vasistha, Navneet A
Zhao, Chen
Burr, Karen
Story, David
Cardinali, Alessandra
Morton, Nicholas M
Hardingham, Giles E
Wyllie, David J A
Chandran, Siddharthan
author_facet Barton, Samantha K
Magnani, Dario
James, Owen G
Livesey, Matthew R
Selvaraj, Bhuvaneish T
James, Owain T
Perkins, Emma M
Gregory, Jenna M
Cleary, Elaine
Ausems, C Rosanne M
Carter, Roderick N Carter
Vasistha, Navneet A
Zhao, Chen
Burr, Karen
Story, David
Cardinali, Alessandra
Morton, Nicholas M
Hardingham, Giles E
Wyllie, David J A
Chandran, Siddharthan
author_sort Barton, Samantha K
collection PubMed
description Oligodendrocytes are implicated in amyotrophic lateral sclerosis pathogenesis and display transactive response DNA-binding protein-43 (TDP-43) pathological inclusions. To investigate the cell autonomous consequences of TDP-43 mutations on human oligodendrocytes, we generated oligodendrocytes from patient-derived induced pluripotent stem cell lines harbouring mutations in the TARDBP gene, namely G298S and M337V. Through a combination of immunocytochemistry, electrophysiological assessment via whole-cell patch clamping, and three-dimensional cultures, no differences in oligodendrocyte differentiation, maturation or myelination were identified. Furthermore, expression analysis for monocarboxylate transporter 1 (a lactate transporter) coupled with a glycolytic stress test showed no deficit in lactate export. However, using confocal microscopy, we report TDP-43 mutation-dependent pathological mis-accumulation of TDP-43. Furthermore, using in vitro patch-clamp recordings, we identified functional Ca(2+)-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor dysregulation in oligodendrocytes. Together, these findings establish a platform for further interrogation of the role of oligodendrocytes and cellular autonomy in TDP-43 proteinopathy.
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spelling pubmed-89364272022-03-28 Transactive response DNA-binding protein-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model Barton, Samantha K Magnani, Dario James, Owen G Livesey, Matthew R Selvaraj, Bhuvaneish T James, Owain T Perkins, Emma M Gregory, Jenna M Cleary, Elaine Ausems, C Rosanne M Carter, Roderick N Carter Vasistha, Navneet A Zhao, Chen Burr, Karen Story, David Cardinali, Alessandra Morton, Nicholas M Hardingham, Giles E Wyllie, David J A Chandran, Siddharthan Brain Commun Original Article Oligodendrocytes are implicated in amyotrophic lateral sclerosis pathogenesis and display transactive response DNA-binding protein-43 (TDP-43) pathological inclusions. To investigate the cell autonomous consequences of TDP-43 mutations on human oligodendrocytes, we generated oligodendrocytes from patient-derived induced pluripotent stem cell lines harbouring mutations in the TARDBP gene, namely G298S and M337V. Through a combination of immunocytochemistry, electrophysiological assessment via whole-cell patch clamping, and three-dimensional cultures, no differences in oligodendrocyte differentiation, maturation or myelination were identified. Furthermore, expression analysis for monocarboxylate transporter 1 (a lactate transporter) coupled with a glycolytic stress test showed no deficit in lactate export. However, using confocal microscopy, we report TDP-43 mutation-dependent pathological mis-accumulation of TDP-43. Furthermore, using in vitro patch-clamp recordings, we identified functional Ca(2+)-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor dysregulation in oligodendrocytes. Together, these findings establish a platform for further interrogation of the role of oligodendrocytes and cellular autonomy in TDP-43 proteinopathy. Oxford University Press 2021-10-26 /pmc/articles/PMC8936427/ /pubmed/35350711 http://dx.doi.org/10.1093/braincomms/fcab255 Text en © The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. https://creativecommons.org/licenses/by/4.0/This 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 reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Barton, Samantha K
Magnani, Dario
James, Owen G
Livesey, Matthew R
Selvaraj, Bhuvaneish T
James, Owain T
Perkins, Emma M
Gregory, Jenna M
Cleary, Elaine
Ausems, C Rosanne M
Carter, Roderick N Carter
Vasistha, Navneet A
Zhao, Chen
Burr, Karen
Story, David
Cardinali, Alessandra
Morton, Nicholas M
Hardingham, Giles E
Wyllie, David J A
Chandran, Siddharthan
Transactive response DNA-binding protein-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model
title Transactive response DNA-binding protein-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model
title_full Transactive response DNA-binding protein-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model
title_fullStr Transactive response DNA-binding protein-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model
title_full_unstemmed Transactive response DNA-binding protein-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model
title_short Transactive response DNA-binding protein-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model
title_sort transactive response dna-binding protein-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8936427/
https://www.ncbi.nlm.nih.gov/pubmed/35350711
http://dx.doi.org/10.1093/braincomms/fcab255
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