Biological psychiatry · 2024
The A53T Mutation in α-Synuclein Enhances Proinflammatory Activation in Human Microglia Upon Inflammatory Stimulus.
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Krzisch Marine, Yuan Bingbing, Chen Wenyu, Osaki Tatsuya, Fu Dongdong, Garrett-Engele Carrie M, Svoboda Devon S, Andrykovich Kristin R, Gallagher Michael D, Sur Mriganka, Jaenisch Rudolf
Аннотация
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.
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.