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Sci. Adv., Apr 11 2025, 11 (15) eadp8504 | https://doi.org/10.1126/sciadv.adp8504
Astrocytic RNA editing regulates the host immune response to alpha-synuclein
Karishma D'Sa 1 2 3 †, Minee L Choi 1 2 3 4 †, Aaron Z Wagen 1 2 3 5 †, Núria Setó-Salvia 1 6, Olga Kopach 7 8, James R Evans 1 2 3, Margarida Rodrigues 9 10, Patricia Lopez-Garcia 1 2 3, Joanne Lachica 1 2 3 11, Benjamin E Clarke 2 12, Jaijeet Singh 1 2, Ali Ghareeb 1 13, James Bayne 13 14, Melissa Grant-Peters 3 5, Sonia Garcia-Ruiz 3 5, Zhongbo Chen 1 2, Samuel Rodriques 13 15, Dilan Athauda 1 2, Emil K Gustavsson 3 5 11, Sarah A Gagliano Taliun 16 17, Christina Toomey 1 2 3 11, Regina H Reynolds 3 5, George Young 2 18, Stephanie Strohbuecker 2 3, Thomas Warner 1 6, Dmitri A Rusakov 7, Rickie Patani 2 12, Clare Bryant 19, David A Klenerman 9 10, Sonia Gandhi 1 2 3 *, Mina Ryten 3 5 10 20 21 *
1Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK.
2The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
3Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA.
4Department of Brain & Cognitive Sciences, KAIST, 921 Dehak-ro, Daejeon, Republic of Korea.
5Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
6Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
7Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
8Neuroscience and Cell Biology Research Institute, City St George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
9Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
10UK Dementia Research Institute at The University of Cambridge, Cambridge CB2 0AH, UK.
11UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
12Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK.
13Applied Biotechnology Lab, The Francis Crick Institute, London NW1 1AT, UK.
14Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK.
15FutureHouse, 1405 Minnesota Street, San Francisco, CA 94107, USA.
16Montréal Heart Institute, Montréal, QC, Canada.
17Department of Medicine and Department of Neurosciences, Université de Montréal, Montréal, QC, Canada.
18MRC Laboratory of Medical Sciences, London W12 0HS, UK.
19Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK.
20Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK.
21Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
2The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
3Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA.
4Department of Brain & Cognitive Sciences, KAIST, 921 Dehak-ro, Daejeon, Republic of Korea.
5Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
6Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
7Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
8Neuroscience and Cell Biology Research Institute, City St George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
9Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
10UK Dementia Research Institute at The University of Cambridge, Cambridge CB2 0AH, UK.
11UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
12Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK.
13Applied Biotechnology Lab, The Francis Crick Institute, London NW1 1AT, UK.
14Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK.
15FutureHouse, 1405 Minnesota Street, San Francisco, CA 94107, USA.
16Montréal Heart Institute, Montréal, QC, Canada.
17Department of Medicine and Department of Neurosciences, Université de Montréal, Montréal, QC, Canada.
18MRC Laboratory of Medical Sciences, London W12 0HS, UK.
19Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK.
20Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK.
21Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
†These authors contributed equally
*Corresponding authors: correspondence to Sonia Gandhi or Mina Ryten
*Corresponding authors: correspondence to Sonia Gandhi or Mina Ryten
Abstract
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.
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- Research article
- 2025년 04월 (BRIC 등록일 2025-05-20)
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