New Insights into Parkinson's Disease: Key Role of RNA Editing Enzyme Uncovered

Recent research has unveiled significant findings regarding Parkinson's disease (PD), a neurodegenerative disorder characterized by the abnormal aggregation of ?-synuclein protein in brain cells, leading to neuronal damage. An international team of researchers from the Korea Advanced Institute of Science and Technology (KAIST), in partnership with University College London and the Francis Crick Institute, has identified the crucial role of RNA editing in regulating neuroinflammation--an essential pathological feature of Parkinson's disease.

Published in the journal Science Advances, the study was led by Professor Minee L. Choi from KAIST's Department of Brain and Cognitive Sciences. The researchers focused on the RNA-editing enzyme ADAR1, which plays a pivotal role in controlling immune responses in astrocytes--glial cells that facilitate protective reactions in the brain. They demonstrated that this mechanism is integral to the progression of Parkinson's disease.

The research team developed a co-culture model consisting of astrocytes and neurons derived from patients with Parkinson's disease to investigate the inflammatory responses of brain immune cells. They treated the model with ?-synuclein aggregates, known to induce Parkinson's disease, and examined the changes in immune cell inflammatory responses.

The findings revealed that early pathological forms of ?-synuclein, referred to as oligomers, activated the Toll-like receptor pathway in astrocytes, functioning as a danger sensor, alongside the interferon response pathway, which is an immune signaling network that combats viruses and pathogens. During this immune response, the RNA editing enzyme ADAR1 was expressed and converted into an isoform with altered protein structure and function.

Significantly, the RNA editing activity of ADAR1, which typically regulates immune responses during viral infections by converting adenosine (A) to inosine (I) through a process known as A-to-I RNA editing, was found to be disproportionately focused on inflammatory genes rather than functioning under normal conditions. This abnormality was observed in both patient-derived neuron models and postmortem brain tissues from individuals diagnosed with Parkinson's disease.

This research provides direct evidence that dysregulated RNA editing leads to chronic inflammatory responses in astrocytes, ultimately resulting in neuronal toxicity and the progression of the disease. The study highlights the regulation of RNA editing within astrocytes as a key mechanism behind neuroinflammatory responses, suggesting that ADAR1 could represent a novel genetic target for Parkinson's disease treatment.

Additionally, the study utilized patient-specific induced pluripotent stem cell models, reflecting actual pathological characteristics found in patients, which enhances the relevance of the findings. Professor Choi noted that this research illustrates how the regulation of inflammation linked to protein aggregation operates through a new layer of RNA editing, presenting a potentially transformative therapeutic strategy for Parkinson's disease treatment. The findings suggest that RNA editing technology could play a critical role in developing new therapeutics aimed at neuroinflammation.