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Transactive response DNA-binding protein-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model.

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.

SUBMITTER: Barton SK

PROVIDER: S-EPMC8936427 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Transactive response DNA-binding protein-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model.

Barton Samantha K SK Magnani Dario D James Owen G OG Livesey Matthew R MR Selvaraj Bhuvaneish T BT James Owain T OT Perkins Emma M EM Gregory Jenna M JM Cleary Elaine E Ausems C Rosanne M CRM Carter Roderick N Carter RNC Vasistha Navneet A NA Zhao Chen C Burr Karen K Story David D Cardinali Alessandra A Morton Nicholas M NM Hardingham Giles E GE Wyllie David J A DJA Chandran Siddharthan S

Brain communications 20211026 4

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 <i>TARDBP</i> gene, namely G298S and M337V. Through a combination of immunocytochemistry, electrophysiological assessment ...[more]

PMID: 35350711

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Project description:ImportanceTransactive response DNA-binding protein 43 (TDP-43) is associated with Alzheimer disease (AD), progressive hippocampal atrophy, and cognitive decline. The apolipoprotein E (APOE) ε4 allele is strongly associated with β-amyloid (Aβ) aggregation and risk of AD, but its association with TDP-43 is unknown.ObjectiveTo determine whether the APOE ε4 allele is a risk factor for TDP-43.Design, setting, participantsThis cross-sectional, genetic-histologic study analyzed APOE genotype, TDP-43 status (positive vs negative), Aβ status (positive vs negative), and tau neurofibrillary tangle stage (B0, Braak stage 0; B1, Braak stages I-II; B2, Braak stages III-IV; B3, Braak stage ≥ V). We fit structural equation models to map the association between APOE and TDP-43, Aβ, and tau, accounting for age and hippocampal sclerosis. We identified 751 participants with an AD pathological spectrum diagnosis and completed Aβ, tau, and TDP-43 data who were enrolled in the Mayo Clinic Alzheimer Disease Research Center, Mayo Clinic Alzheimer Disease Patient Registry, or the population based Mayo Clinic Study of Aging and died between May 12, 1999, and December 31, 2015. However, 13 were excluded from the analyses because of missing APOE data, leaving a total of 738 participants.Main outcomes and measuresTransactive response DNA-binding protein 43 was the main outcome of interest. We hypothesized that the APOE ε4 allele would be significantly directly and indirectly associated with TDP-43.ResultsThe 751 study participants were older (median age [interquartile range], 87 years [51-105 years]), 395 (54%) were women, and 324 (44%) were APOE ε4 carriers. The patients died between May 12, 1999, and December 31, 2015. Accounting for age, Aβ, and tau, APOE ε4 had a direct association with TDP-43 (estimate [SE], 0.31 (0.11); P = .01). The association was present among individuals with an intermediate to high likelihood of having AD (neurofibrillary tangle stage B2/B3; n = 604 [81.8%]; estimate [SE], 0.51 [0.11]; P < .001), with a similar trend for those with a low likelihood of having AD (B1; n = 134 [18.2%]; estimate [SE], 0.54 [0.32]; P = .10). We also found an indirect association of APOE ε4 with TDP-43 via Aβ and tau (estimate [SE], 0.34 [0.06]; P < .001), which was similar in magnitude to the direct association and an indirect association of APOE ε4 with hippocampal sclerosis via TDP-43 (estimate [SE], 0.65 [0.26]; P = .01).Conclusions and relevanceThe study's findings, which mapped a system of risk factors and outcomes, showed that the APOE ε4 allele appears to be a risk factor for TDP-43 independently of Aβ in patients with AD.

Dataset Information

Transactive response DNA-binding protein-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model.

Publications

Transactive response DNA-binding protein-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model.

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