Back to Search
Start Over
Transactive response DNA-binding protein-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model.
- Source :
-
Brain communications [Brain Commun] 2021 Oct 26; Vol. 3 (4), pp. fcab255. Date of Electronic Publication: 2021 Oct 26 (Print Publication: 2021). - Publication Year :
- 2021
-
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 Ca <superscript>2+</superscript> -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.<br /> (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)
Details
- Language :
- English
- ISSN :
- 2632-1297
- Volume :
- 3
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Brain communications
- Publication Type :
- Academic Journal
- Accession number :
- 35350711
- Full Text :
- https://doi.org/10.1093/braincomms/fcab255