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

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


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


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


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