Parkinson's disease (PD), the second most common neurodegenerative disorder, was characterized by alpha-synuclein pathology and dopaminergic neuron degeneration. In previous studies, multiple genes have been demonstrated to involve in the regulations of these two processes, including EIF2AK2, AGO2, MCL1, EEF1A1, and AIMP2. The molecular mechanisms to mediate the transcript diversity of these genetic biomarkers were important to understand neurodegenerative pathogenesis and helpful for treatment design. In this study, we analyzed 372 PD patients to identify 9,897 A-to-I RNA editing events probably responsible for the controls of 6,286 genes. Due to the most potentially trans-regulatory associations between RNA editing events and genes, we tried to explain one possible pathway from the view of disturbed miRNA regulations on genes due to A-to-I RNA editing events. Specifically, we identified 72 RNA editing events probably interfering in miRNA regulations on their host genes, eight RNA editing events possibly altering miRNA competitions between their host genes and 1,146 other genes, and one RNA editing event modifying miRNA seed regions to potentially disturb its regulations on four genes. All the analyses revealed 25 RNA editing biomarkers in Parkinson's pathogenesis through probably interfering in miRNA degradations on 133 PD-related genes.
A-to-I RNA editing diversifies human transcriptome to confer its functional effects on the downstream genes or regulations, potentially involving in neurodegenerative pathogenesis. Its variabilities are attributed to multiple regulators, including the key factor of genetic variants. To comprehensively investigate the potentials of neurodegenerative disease-susceptibility variants from the view of A-to-I RNA editing, we analyzed matched genetic and transcriptomic data of 1596 samples across nine brain tissues and whole blood from two large consortiums, Accelerating Medicines Partnership-Alzheimer’s Disease and Parkinson’s Progression Markers Initiative. The large-scale and genome-wide identification of 95 198 RNA editing quantitative trait loci revealed the preferred genetic effects on adjacent editing events. Furthermore, to explore the underlying mechanisms of the genetic controls of A-to-I RNA editing, several top RNA-binding proteins were pointed out, such as EIF4A3, U2AF2, NOP58, FBL, NOP56 and DHX9, since their regulations on multiple RNA-editing events were probably interfered by these genetic variants. Moreover, these variants may also contribute to the variability of other molecular phenotypes associated with RNA editing, including the functions of 3 proteins, expressions of 277 genes and splicing of 449 events. All the analyses results shown in NeuroEdQTL (https://relab.xidian.edu.cn/NeuroEdQTL/) constituted a unique resource for the understanding of neurodegenerative pathogenesis from genotypes to phenotypes related to A-to-I RNA editing.
A-to-I RNA editing diversifies human transcriptome to confer its functional effects on the downstream genes or regulations, potentially involving in neurodegenerative pathogenesis. Its variabilities are attributed to multiple regulators, including the key factor of genetic variant. To comprehensively investigate the potentials of neurodegenerative disease-susceptibility variants from the view of A-to-I RNA editing, we analyzed matched genetic and transcriptomic data of 1,596 samples across nine brain tissues and whole blood from two large consortiums, Accelerating Medicines Partnership - Alzheimer's Disease (AMP-AD) and Parkinson's Progression Markers Initiative (PPMI). The large-scale and genome-wide identification of 95,637 RNA editing quantitative trait loci revealed the preferred genetic effects on adjacent editing events. Furthermore, to explore the underlying mechanisms of the genetic controls of A-to-I RNA editing, several top RNA binding proteins were pointed out, such as EIF4A3, U2AF2, NOP58, FBL, NOP56, and DHX9, since their regulations on multiple RNA editing events probably interfered by these genetic variants. Moreover, these variants may also contribute to the variability of other molecular phenotypes associated with RNA editing, including the functions of four proteins, expressions of 148 genes, and splicing of 417 events. All the analyses results shown in NeuroEdQTL (https://relab.xidian.edu.cn/NeuroEdQTL/) constituted a unique resource for the understanding of neurodegenerative pathogenesis from genotypes to phenotypes related to A-to-I RNA editing.
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.
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