posted on 2025-04-14, 11:32authored byKarishma D'Sa, Minee L Choi, Aaron Z Wagen, Núria Setó-Salvia, Olga Kopach, James R Evans, Margarida Rodrigues, Patricia Lopez-Garcia, Joanne Lachica, Benjamin E Clarke, Jaijeet Singh, Ali Ghareeb, James Bayne, Melissa Grant-Peters, Sonia Garcia-Ruiz, Zhongbo Chen, Samuel Rodriques, Dilan Athauda, Emil K Gustavsson, Sarah A Gagliano Taliun, Christina Toomey, Regina H Reynolds, George Young, Stephanie Strohbuecker, Thomas Warner, Dmitri A Rusakov, Rickie Patani, Clare Bryant, David A Klenerman, Sonia Gandhi, Mina Ryten
RNA editing is a posttranscriptional mechanism that targets changes in RNA transcripts to modulate innate immune responses. We report the role of astrocyte-specific, ADAR1-mediated RNA editing in neuroinflammation in Parkinson's disease (PD). We generated human induced pluripotent stem cell-derived astrocytes, neurons and cocultures and exposed them to small soluble alpha-synuclein aggregates. Oligomeric alpha-synuclein triggered an inflammatory glial state associated with Toll-like receptor activation, viral responses, and cytokine secretion. This reactive state resulted in loss of neurosupportive functions and the induction of neuronal toxicity. Notably, interferon response pathways were activated leading to up-regulation and isoform switching of the RNA deaminase enzyme, ADAR1. ADAR1 mediates A-to-I RNA editing, and increases in RNA editing were observed in inflammatory pathways in cells, as well as in postmortem human PD brain. Aberrant, or dysregulated, ADAR1 responses and RNA editing may lead to sustained inflammatory reactive states in astrocytes triggered by alpha-synuclein aggregation, and this may drive the neuroinflammatory cascade in Parkinson's.
Funding
Crick (Grant ID: CC2168, Grant title: Rodriques CC2168)
Crick (Grant ID: CC1107, Grant title: STP Bioinformatics & Biostatistics)