Krzisch, M., Yuan, B., Chen, W. et al. (8 more authors) (2025) The A53T mutation in α-synuclein enhances pro-inflammatory activation in human microglia upon inflammatory stimulus. Biological Psychiatry, 97 (7). pp. 730-742. ISSN 0006-3223
Abstract
Background Parkinson’s disease (PD) is the second most common neurodegenerative disease, following Alzheimer’s. It is characterized by the aggregation of α-synuclein into Lewy bodies and Lewy neurites in the brain. Microglia-driven neuroinflammation may contribute to neuronal death in PD; however, the exact role of microglia remains unclear and has been understudied. The A53T mutation in the gene coding for α-synuclein has been linked to early-onset PD, and exposure to A53T mutant human α-synuclein increases the potential for inflammation of murine microglia. To date, its effect has not been studied in human microglia. Methods Here, we used 2-dimensional cultures of human pluripotent stem cell–derived microglia and transplantation of these cells into the mouse brain to assess the cell autonomous effects of the A53T mutation on human microglia. Results We found that A53T mutant human microglia had an intrinsically increased propensity toward proinflammatory activation upon inflammatory stimulus. Additionally, transplanted A53T mutant microglia showed a strong decrease in catalase expression in noninflammatory conditions and increased oxidative stress. Conclusions Our results indicate that A53T mutant human microglia display cell autonomous phenotypes that may worsen neuronal damage in early-onset PD.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | Crown Copyright © 2024. This is an open access article under the terms of the Creative Commons Attribution License (CC-BY-NC-ND 4.0). |
Keywords: | Disease modeling, Human pluripotent stem cells, Inflammation, Microglia, Parkinson’s disease, Xenotransplantation |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 05 Aug 2024 10:37 |
Last Modified: | 27 Mar 2025 10:06 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.biopsych.2024.07.011 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:215677 |