The Potential Regulation of A-to-I RNA Editing on Genes in Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is characterized by dopaminergic neurodegeneration and an abnormal accumulation of α-synuclein aggregates. A number of genetic factors have been shown to increase the risk of PD. Exploring the underlying molecular mechanisms that mediate PD’s transcriptomic diversity can help us understand neurodegenerative pathogenesis. In this study, we identified 9897 A-to-I RNA editing events associated with 6286 genes across 372 PD patients. Of them, 72 RNA editing events altered miRNA binding sites and this may directly affect miRNA regulations of their host genes. However, RNA editing effects on the miRNA regulation of genes are more complex. They can (1) abolish existing miRNA binding sites, which allows miRNAs to regulate other genes; (2) create new miRNA binding sites that may sequester miRNAs from regulating other genes; or (3) occur in the miRNA seed regions and change their targets. The first two processes are also referred to as miRNA competitive binding. In our study, we found 8 RNA editing events that may alter the expression of 1146 other genes via miRNA competition. We also found one RNA editing event that modified a miRNA seed region, which was predicted to disturb the regulation of four genes. Considering the PD-related functions of the affected genes, 25 A-to-I RNA editing biomarkers for PD are proposed, including the 3 editing events in the EIF2AK2, APOL6, and miR-4477b seed regions. These biomarkers may alter the miRNA regulation of 133 PD-related genes. All these analyses reveal the potential mechanisms and regulations of RNA editing in PD pathogenesis.

Early-stage idiopathic Parkinson’s disease is associated with reduced circular RNA expression

“…ADAR was significantly increased in PPMI PD cases and showed a similar trend in ICICLE-PD (Supplementary Data 11 ). Although ADAR expression levels do not necessarily correlate with editing activity 79 , altered RNA editing has been observed in PD patients’ blood and brain regions 61 , 80 . RNase L degrades circRNAs as a response to viral infection 50 .…”

The role of ADAR editing and nonsense-mediated decay in Parkinson’s Disease

“…ADAR2 and 3 expression was also highest in either prodromal or PD samples depending on whether sexes are combined. Other studies have observed decreased editing frequency [121] and significant differences in ADAR expression [122] in PPMI PD blood; however, these studies did not compare PD males to PD females or PD to prodromal in their analyses and included samples regardless of age; whereas, we chose samples from individuals 65 years or older.…”

“…Additionally, alterations in ADAR editing at 57 sites correlated with the progression of cognitive symptoms in PD patients [122]. In another study of PPMI whole blood transcriptomes, 72 ADAR editing events were observed that affected miRNA binding, 8 of which may alter the expression of many other genes [121]. Editing within seed regions of miRNA transcripts can potentially change editing targets and cause further dysregulation of gene expression [121].…”

“…In another study of PPMI whole blood transcriptomes, 72 ADAR editing events were observed that affected miRNA binding, 8 of which may alter the expression of many other genes [121]. Editing within seed regions of miRNA transcripts can potentially change editing targets and cause further dysregulation of gene expression [121]. ADAR editing has also been associated with AD and PD in a study of blood and brain samples from both AD and PPMI PD patients identifying 198 loci in protein coding regions, of which 35 are potentially related to neurodegeneration [140].…”