Open AccessTDP-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model
Author(s) -
Samantha K. Barton,
Dario Magnani,
Owen G James,
Matthew R. Livesey,
Bhuvaneish T. Selvaraj,
Owain T. James,
Emma M. Perkins,
Jenna M Gregory,
Elaine M. Cleary,
C Rosanne M Ausems,
Roderick N Carter Carter,
Navneet A. Vasistha,
Chen Zhao,
Karen Burr,
David Story,
Alessandra Cardinali,
Nicholas M. Morton,
Giles E. Hardingham,
David J. A. Wyllie,
Siddharthan Chandran
Publication year - 2021
Publication title -
brain communications
Language(s) - English
Resource type - Journals
ISSN - 2632-1297
DOI - 10.1093/braincomms/fcab255
Subject(s) - microbiology and biotechnology , induced pluripotent stem cell , biology , neuroscience , immunocytochemistry , oligodendrocyte , myelin , genetics , gene , central nervous system , embryonic stem cell , endocrinology
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.