Objective: 1) Using an IPSC derived cell model to explore astrocytic responses alone and cocultured neurons to alpha-synuclein oligomer (αsynO) treatment.

2) Determine the extent to which RNA editing contributes to this response.

Background: Inflammation is increasingly implicated in the early pathogenesis and progression of Parkinson’s disease (PD).^1,2 A-to-I RNA editing is a post-translational modification to RNA mediated by adenosine deaminase acting on RNA (ADAR), and hypothesised to dampen the type 1 interferon response.³ Here we explore the relationship of α-synO treatment with the type 1 interferon response in astrocytes and neurons, including A-to-I editing.

Method: Induced pluripotent stem cell (IPSC) derived astrocytes from 5 different donors, neurons from a further donor, and co-cultures of each of these lines, were treated with α-synO, followed by with single-cell and bulk RNA-sequencing. Editing sites and rate were assessed with JACUSA2.⁴

Results: α-synO treatment triggered an increase in inflammatory cytokines in astrocytes cultured alone and in co-culture with neurons. Treatment resulted in a significant increase in an inflammatory subclass of astrocytes, with increased expression of genes and proteins relating to the viral and type 1 interferon response. This included an increase in ADAR1 expression and a change in isoform use. Treated cultures had significantly higher expression of the inflammation-associated p150 isoform with a significant increase in the number of editing sites and editing rate. Differentially edited sites were predominately in 3’ untranslated regions and we noted that genes with higher numbers of editing sites showed smaller changes in gene expression on treatment with α-synO.

Conclusion: There was a type 1 interferon response to α-synO treatment in astrocytes and astrocyte-neuron co-cultures. This response was associated with an increase in RNA editing, with the functional consequence being to dampen gene expression changes associated with α-synO treatment. These results support an important role for innate immune responses in the pathogenesis of PD and suggest that modulation of the interferon response through RNA editing could represent a novel therapeutic strategy.

References: 1.    Kouli, A. & Williams-Gray, C. H. Age-Related Adaptive Immune Changes in Parkinson’s Disease. J Parkinsons Dis 12, S93–S104 (2022).
2.    Hughes, C. D. et al. Picomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson’s disease pathogenesis. Acta Neuropathol. 137, 103–120 (2019).
3.    Nishikura, K. A-to-I editing of coding and non-coding RNAs by ADARs. Nat. Rev. Mol. Cell Biol. 17, 83–96 (2016).
4.    Piechotta, M., Naarmann-de Vries, I. S., Wang, Q., Altmüller, J. & Dieterich, C. RNA modification mapping with JACUSA2. Genome Biol. 23, 115 (2022).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/rna-editing-contributes-to-the-inflammatory-astrocytic-response-in-parkinsons-disease/