TY - JOUR
T1 - TDP-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model
AU - Barton, Samantha K
AU - Magnani, Dario
AU - James, Owen G
AU - Livesey, Matthew R
AU - Selvaraj, Bhuvaneish T
AU - James, Owain T
AU - Perkins, Emma M
AU - Gregory, Jenna M
AU - Cleary, Elaine
AU - Ausems, C Rosanne M
AU - Carter, Rod
AU - Vasistha, Navneet A
AU - Zhao, Chen
AU - Burr, Karen
AU - Story, David
AU - Cardinali, Alessandra
AU - Morton, Nicholas M
AU - Hardingham, Giles E
AU - Wyllie, David J A
AU - Chandran, Siddharthan
PY - 2021/10/26
Y1 - 2021/10/26
N2 - 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.
AB - 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.
KW - amyotrophic lateral sclerosis
KW - oligodendrocytes
KW - TDP-43
KW - induced pluripotent stem cell
U2 - 10.1093/braincomms/fcab255
DO - 10.1093/braincomms/fcab255
M3 - Article
VL - 3
JO - Brain Communications
JF - Brain Communications
IS - 4
M1 - fcab255
ER -