Astrocytic RNA editing regulates the host immune response to alpha-synuclein.
Karishma D'Sa1,2,3, Minee L Choi1,2,3,4, Aaron Z Wagen1,2,3,5
1Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Science Advances
|April 11, 2025
Summary
Astrocyte-specific RNA editing, mediated by ADAR1, plays a key role in Parkinson's disease neuroinflammation. Dysregulated ADAR1 responses to alpha-synuclein contribute to sustained inflammation and neuronal toxicity in Parkinson's disease.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- RNA editing is a crucial posttranscriptional mechanism modulating innate immunity.
- Parkinson's disease (PD) involves neuroinflammation, but the underlying RNA editing mechanisms are not fully understood.
Purpose of the Study:
- To investigate the role of astrocyte-specific ADAR1-mediated RNA editing in the neuroinflammatory response in Parkinson's disease.
Main Methods:
- Generated human induced pluripotent stem cell-derived astrocytes, neurons, and cocultures.
- Exposed cells to soluble alpha-synuclein aggregates.
- Analyzed RNA editing changes and inflammatory markers in cellular and postmortem PD brain samples.
Main Results:
- Alpha-synuclein aggregates induced a reactive glial state with activated inflammatory and viral response pathways.
- Interferon response pathways led to ADAR1 up-regulation and isoform switching.
- Increased RNA editing was observed in inflammatory pathways in cells and postmortem PD brain tissue.
Conclusions:
- Dysregulated ADAR1 responses and RNA editing contribute to sustained astrocyte inflammation triggered by alpha-synuclein.
- This aberrant RNA editing may drive the neuroinflammatory cascade observed in Parkinson's disease.
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