Variations in ADAR editing of nonsense-mediated decay targets in PD males and females

<ns3:p>Background Parkinson’s Disease (PD) is a complex disease with multiple phenotypes varying between individuals, as well as by age and sex. Males are diagnosed with PD at a much higher rate than females, and females experience later onset yet faster disease progression than males; the sexes also differ in PD by neuron composition, gene expression, and symptom progression. Because only a fraction of PD cases can be tied to genetic variants, it is likely that a complicated interaction between gene expression, hormones, the environment, and modifications to RNA transcripts plays a role in PD pathology and progression. Methods Here we explored changes in RNA editing through analysis of RNAseq between 243 healthy controls and PD patients aged 65 years or older enrolled in the Parkinson’s Progression Markers Initiative. Specifically, we analyzed editing through the actions of the adenosine deaminases acting on RNA (ADARs), which may cause nonsynonymous alterations to gene expression products including those that result in nonsense-mediated decay (NMD). Results We observe differences in ADAR expression, number of putative ADAR edits, and the number of high/moderate impact edits between comparison groups and PD samples, which often show higher levels of ADAR expression and edits. PD males and females also differ in ADAR expression, number of edits, and the number of high and moderate impact edits with males exhibiting elevations compared to females in all three categories except in those edits associated with NMD, particularly in edits affecting SLC11A2, a gene coding for a transmembrane iron transporter. Likewise, differentially expressed genes between comparison groups were tied to NMD-related pathways Conclusion Our findings suggest that the dysregulation of ADAR editing may play a role in PD and that ADAR editing associated with NMD and genes functioning in NMD-related pathways may be integral to PD pathophysiology, particularly when comparing the sexes.</ns3:p>