Details

Autor(en) / Beteiligte

• 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, Rod
• Vasistha, Navneet A
• Zhao, Chen
• Burr, Karen
• Story, David
• Cardinali, Alessandra
• Morton, Nicholas M
• Hardingham, Giles E
• Wyllie, David J A
• Chandran, Siddharthan

Titel

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

Ist Teil von

• Brain communications, 2021-10

Erscheinungsjahr

2021

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Abstract Oligodendrocytes are implicated in Amytrophic Lateral Sclerosis pathogenesis and display 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. Further, 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 AMPA 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.