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

Samantha K.  Barton; Jenna Gregory; Dario Magnani; Owen G.  James; Matthew R. Livesey; Bhuvaneish T.  Selvaraj; Owain T. James; Emma M. Perkins; Elaine M. Cleary; C Rosanne M  Ausems; Roderick N.  Carter; Navneet A. Vasistha; Chen-Ru Zhao; Karen Burr; David Story; Alessandra  Cardinali; Nicholas M. Morton; Giles E.  Hardingham; David J. A.  Wyllie; Siddharthan Chandran

doi:10.1093/braincomms/fcab255

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

Samantha K. Barton^* (Corresponding Author), Jenna Gregory, Dario Magnani, Owen G. James, Matthew R. Livesey, Bhuvaneish T. Selvaraj, Owain T. James, Emma M. Perkins, Elaine M. Cleary, C Rosanne M Ausems, Roderick N. Carter, Navneet A. Vasistha, Chen-Ru Zhao, Karen Burr, David Story, Alessandra Cardinali, Nicholas M. Morton, Giles E. Hardingham, David J. A. Wyllie, Siddharthan Chandran

^*Corresponding author for this work

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Abstract

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 Ca2þpermeable a-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.

Original language	English
Article number	fcab255
Number of pages	12
Journal	Brain Communications
Volume	3
Issue number	4
Early online date	26 Oct 2021
DOIs	https://doi.org/10.1093/braincomms/fcab255
Publication status	Published - 2021

Bibliographical note

Acknowledgements
The authors kindly acknowledge the technical expertise and
assistance of Ms Nicola Miller and Ms Karen Gladstone.
Graphical abstract was created using BioRender.com.
Funding
This research was supported by the Wellcome Trust
(092742/Z/10/Z), MND Association (Miles/Oct14/878–
792), SC lab is supported by the Euan MacDonald Centre
for Motor Neurone Disease Research, and the UK Dementia
Research Institute (DRI), which receives its funding from UK
DRI Ltd, funded by the MRC, Alzheimer’s Society and
Alzheimer’s Research UK. SC also acknowledges funding
from the ARRNC, Department of Biotechnology India,
University of Edinburgh Institutional Strategic Support Fund.
Royal Society of Edinburgh (M.R.L), WT NIA 100981/Z/
13/Z (N.M.M.), ARRNC (B.T.S) and an Australian
National Health and Medical Research (NH&MRC) and
Australian Research Council (ARC) Dementia Research
Development Fellowship (S.K.B.: 1110040)

Keywords

amyotrophic lateral sclerosis
oligodendrocytes
TDP-43
induced pluripotent stem cell

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Barton, S. K., Gregory, J., Magnani, D., James, O. G., Livesey, M. R., Selvaraj, B. T., James, O. T., Perkins, E. M., Cleary, E. M., Ausems, C. R. M., Carter, R. N., Vasistha, N. A., Zhao, C.-R., Burr, K., Story, D., Cardinali, A., Morton, N. M., Hardingham, G. E., Wyllie, D. J. A., & Chandran, S. (2021). Transactive response DNA-binding protein-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model. Brain Communications, 3(4), Article fcab255. https://doi.org/10.1093/braincomms/fcab255

Barton, SK, Gregory, J, Magnani, D, James, OG, Livesey, MR, Selvaraj, BT, James, OT, Perkins, EM, Cleary, EM, Ausems, CRM, Carter, RN, Vasistha, NA, Zhao, C-R, Burr, K, Story, D, Cardinali, A, Morton, NM, Hardingham, GE, Wyllie, DJA & Chandran, S 2021, 'Transactive response DNA-binding protein-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model', Brain Communications, vol. 3, no. 4, fcab255. https://doi.org/10.1093/braincomms/fcab255

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

abstract = "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 Ca2{\th}permeable a-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.",

keywords = "amyotrophic lateral sclerosis, oligodendrocytes, TDP-43, induced pluripotent stem cell",

author = "Barton, {Samantha K.} and Jenna Gregory and Dario Magnani and James, {Owen G.} and Livesey, {Matthew R.} and Selvaraj, {Bhuvaneish T.} and James, {Owain T.} and Perkins, {Emma M.} and Cleary, {Elaine M.} and Ausems, {C Rosanne M} and Carter, {Roderick N.} and Vasistha, {Navneet A.} and Chen-Ru Zhao and Karen Burr and David Story and Alessandra Cardinali and Morton, {Nicholas M.} and Hardingham, {Giles E.} and Wyllie, {David J. A.} and Siddharthan Chandran",

note = "Acknowledgements The authors kindly acknowledge the technical expertise and assistance of Ms Nicola Miller and Ms Karen Gladstone. Graphical abstract was created using BioRender.com. Funding This research was supported by the Wellcome Trust (092742/Z/10/Z), MND Association (Miles/Oct14/878– 792), SC lab is supported by the Euan MacDonald Centre for Motor Neurone Disease Research, and the UK Dementia Research Institute (DRI), which receives its funding from UK DRI Ltd, funded by the MRC, Alzheimer{\textquoteright}s Society and Alzheimer{\textquoteright}s Research UK. SC also acknowledges funding from the ARRNC, Department of Biotechnology India, University of Edinburgh Institutional Strategic Support Fund. Royal Society of Edinburgh (M.R.L), WT NIA 100981/Z/ 13/Z (N.M.M.), ARRNC (B.T.S) and an Australian National Health and Medical Research (NH&MRC) and Australian Research Council (ARC) Dementia Research Development Fellowship (S.K.B.: 1110040)",

year = "2021",

doi = "10.1093/braincomms/fcab255",

language = "English",

volume = "3",

journal = "Brain Communications",

issn = "2632-1297",

publisher = "Oxford University Press (OUP)",

number = "4",

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TY - JOUR

T1 - Transactive response DNA-binding protein-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model

AU - Barton, Samantha K.

AU - Gregory, Jenna

AU - Magnani, Dario

AU - James, Owen G.

AU - Livesey, Matthew R.

AU - Selvaraj, Bhuvaneish T.

AU - James, Owain T.

AU - Perkins, Emma M.

AU - Cleary, Elaine M.

AU - Ausems, C Rosanne M

AU - Carter, Roderick N.

AU - Vasistha, Navneet A.

AU - Zhao, Chen-Ru

AU - Burr, Karen

AU - Story, David

AU - Cardinali, Alessandra

AU - Morton, Nicholas M.

AU - Hardingham, Giles E.

AU - Wyllie, David J. A.

AU - Chandran, Siddharthan

N1 - Acknowledgements The authors kindly acknowledge the technical expertise and assistance of Ms Nicola Miller and Ms Karen Gladstone. Graphical abstract was created using BioRender.com. Funding This research was supported by the Wellcome Trust (092742/Z/10/Z), MND Association (Miles/Oct14/878– 792), SC lab is supported by the Euan MacDonald Centre for Motor Neurone Disease Research, and the UK Dementia Research Institute (DRI), which receives its funding from UK DRI Ltd, funded by the MRC, Alzheimer’s Society and Alzheimer’s Research UK. SC also acknowledges funding from the ARRNC, Department of Biotechnology India, University of Edinburgh Institutional Strategic Support Fund. Royal Society of Edinburgh (M.R.L), WT NIA 100981/Z/ 13/Z (N.M.M.), ARRNC (B.T.S) and an Australian National Health and Medical Research (NH&MRC) and Australian Research Council (ARC) Dementia Research Development Fellowship (S.K.B.: 1110040)

PY - 2021

Y1 - 2021

N2 - 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 Ca2þpermeable a-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.

AB - 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 Ca2þpermeable a-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.

KW - amyotrophic lateral sclerosis

KW - oligodendrocytes

KW - TDP-43

KW - induced pluripotent stem cell

UR - http://dx.doi.org/10.1093/braincomms/fcab255

U2 - 10.1093/braincomms/fcab255

DO - 10.1093/braincomms/fcab255

M3 - Article

SN - 2632-1297

VL - 3

JO - Brain Communications

JF - Brain Communications

IS - 4

M1 - fcab255

ER -

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

Abstract

Bibliographical note

Keywords

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