RNA Editing's Role in Neuroinflammation in Parkinson's Disease
KAIST researchers identify RNA editing enzyme ADAR1 as a key player in neuroinflammation in Parkinson's disease.
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Parkinson's disease (PD) is a neurodegenerative condition marked by the abnormal aggregation of the α-synuclein protein within brain cells, leading to neuronal damage. Recent research from the Korea Advanced Institute of Science and Technology (KAIST) reveals that RNA editing plays a role in modulating neuroinflammation, a critical factor in the disease's progression.
RNA editing enzyme's role in Parkinson's disease
The study, led by Professor Minee L. Choi from the KAIST Department of Brain and Cognitive Sciences, in collaboration with University College London (UCL) and the Francis Crick Institute, identifies the RNA editing enzyme ADAR1 as a key regulator of immune responses in astrocytes. These glial cells play a protective role in the brain by activating immune responses. The researchers found that ADAR1's role in RNA editing contributes significantly to the inflammation seen in Parkinson’s disease.
RNA editing
A process where RNA molecules are chemically modified after transcription, typically converting adenosine to inosine, which can affect gene expression and protein function.
The team developed a co-culture model combining astrocytes and neurons derived from induced pluripotent stem cells (iPSCs) of Parkinson’s disease patients. This model allowed them to study the inflammatory responses of brain immune cells. The researchers exposed the model to α-synuclein aggregates, known to be involved in Parkinson’s disease pathology, and analyzed how these immune cells responded.
Astrocytes
A type of glial cell in the brain that provides support and protection to neurons and plays a role in the brain's immune response.
Findings from the co-culture model
The results showed that α-synuclein oligomers, an early pathological form of the protein, activated both the Toll-like receptor and interferon response pathways in astrocytes. These pathways serve as critical immune sensors in the brain. During this immune activation, ADAR1 was expressed and altered into an isoform with a different protein structure, suggesting a modification of its function.
Toll-like receptor pathway
A key component of the innate immune system that detects pathogens and activates immune responses.
Interferon response pathway
An immune signaling pathway activated by viral infections and other cellular stressors to combat pathogens.
ADAR1's normal function involves regulating immune responses during viral infections by converting adenosine to inosine, a process known as A-to-I RNA editing. However, in the context of Parkinson’s disease, this RNA editing activity was abnormally focused on genes that promote inflammation, rather than responding to viral threats. This was evident not only in the stem cell-derived neuronal models but also in postmortem brain tissues from Parkinson's disease patients, providing direct evidence of the enzyme's dysregulation in the disease.
Implications for Parkinson’s disease therapy
This study offers insights into how the regulation of RNA editing within astrocytes may drive neuroinflammation in Parkinson’s disease. The findings suggest that targeting ADAR1 could present a novel approach to treating the neuroinflammation associated with the disease. The use of patient-specific iPSC-based models highlights the relevance of the research to human pathology, enhancing the study's translational potential.
"This study demonstrates that the regulator of inflammation caused by protein aggregation operates at the new layer of RNA editing, offering a completely different therapeutic strategy from existing approaches to Parkinson's disease treatment." She further emphasized, “RNA editing technology could become an important turning point in the development of therapeutics for neuroinflammation.”
Professor Minee L. Choi.
Reference: D’Sa K, Choi ML, Wagen AZ, et al. Astrocytic RNA editing regulates the host immune response to alpha-synuclein. Sci Adv. 2025;11(15):eadp8504. doi: 10.1126/sciadv.adp8504
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