Human microglia carrying an early-onset Parkinson's disease mutation display cell-autonomous disease-relevant phenotypes that may worsen neuronal damage
Parkinson's disease (PD) is characterized by the aggregation of a-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 a-synuclein has been linked to early-onset PD, and exposure to A53T-mutant human a-synuclein increases the potential for inflammation of murine microglia. To date, its effect has not been studied in human microglia. We aimed to study the impact of the A53T mutation on human microglia developed in a physiologically relevant context Here, we used 2-dimensional cultures of human iPSC-derived microglia and transplantation of these cells into the mouse brain to assess the effects of the A53T mutation on human microglia. We found that A53T-mutant human microglia had an intrinsically increased propensity towards pro-inflammatory activation upon inflammatory stimulus. Additionally, A53T mutant microglia showed increased oxidative stress, with a strong decrease in catalase expression in non-inflammatory conditions. Together, these results indicate that A53T mutant human microglia display cell-autonomous phenotypes that may worsen neuronal damage in early-onset PD. Overall design: 3 isogenics pairs of A53-mutant (PD)/control microglia were used in this study. Each cell line was differentiated separately, or transplanted into a separate cohort of mice. The RNA was either extracted directly from the cultured cells, or the transplanted cells were extracted from the mouse brain using GFP labeling and the RNA was subsequently extracted for each cell line.