Astrocytic RNA editing regulates the host immune response to alpha-synuclein

Abstract
RNA editing is a post transcriptional 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. We generated hiPSC-derived astrocytes, neurons and co-cultures and exposed them to small soluble alpha-synuclein aggregates. Oligomeric alpha-synuclein triggered an inflammatory glial state associated with TLR 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 upregulation, 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 post-mortem 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.
Competing Interest Statement
Author RHR is currently employed by CoSyne Therapeutics (Lead Bioinformatician). All work performed for this publication was performed in her own time, and not as a part of her duties as an employee. The authors declare no other competing interests.
Footnotes
↵* Joint Authors
Licence : CC-BY 4.0
License updated; Materials and methods updated to clarify oligomer generation and characterisation; Supplemental material and Acknowledgements updated
Subject Area
- Biochemistry (13873)
- Bioengineering (10577)
- Bioinformatics (33605)
- Biophysics (17316)
- Cancer Biology (14383)
- Cell Biology (20369)
- Clinical Trials (138)
- Developmental Biology (10984)
- Ecology (16213)
- Epidemiology (2067)
- Evolutionary Biology (20520)
- Genetics (13518)
- Genomics (18813)
- Immunology (13943)
- Microbiology (32497)
- Molecular Biology (13527)
- Neuroscience (70875)
- Paleontology (533)
- Pathology (2222)
- Pharmacology and Toxicology (3779)
- Physiology (5959)
- Plant Biology (12161)
- Synthetic Biology (3402)
- Systems Biology (8242)
- Zoology (1870)