TDP-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model

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

Research output: Contribution to journalArticlepeer-review

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+-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.
Original languageEnglish
Article numberfcab255
JournalBrain Communications
Volume3
Issue number4
Early online date26 Oct 2021
DOIs
Publication statusE-pub ahead of print - 26 Oct 2021

Keywords

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

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