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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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 languageEnglish
Article numberfcab255
Number of pages12
JournalBrain Communications
Issue number4
Early online date26 Oct 2021
Publication statusPublished - 2021

Bibliographical note

The authors kindly acknowledge the technical expertise and
assistance of Ms Nicola Miller and Ms Karen Gladstone.
Graphical abstract was created using
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)


  • amyotrophic lateral sclerosis
  • oligodendrocytes
  • TDP-43
  • induced pluripotent stem cell


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