A Systematic Review of Common and Brain-Disease-Specific RNA Editing Alterations Providing Novel Insights into Neurological and Neurodegenerative Disease Manifestations
Abstract
1. Introduction
2. Materials and Methods
2.1. Literature Search Strategy
2.2. Eligibility Criteria
2.3. Statistical Analysis and Data Extraction
2.4. Registration for Studies
3. Results
4. Discussion
4.1. The Diagnostic/Prognostic Potential of RNA Editing in Neurological/Neurodegenerative and Psychiatric Disorders
4.2. Future Perspectives and Challenges in the RNA Editing Research Field
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Disorder | Species/Brain Region | Study Type/Target(s) | Methodology/Validation Method | DE Targets/Trend Relative to Controls | Remarks | Ref. |
---|---|---|---|---|---|---|
Epilepsy | Human/HPC | Focused/Grik2 | RFLPs | Grik2: ↑ Q/R site | Suggested as a compensatory mechanism | [27] |
Human/TC | Focused/Grik1 and Grik2 | RFLPs | Grik1: ↑ Q/R site Grik2: ↑ Q/R site | Suggested as a compensatory mechanism | [28] | |
Human/HPC | Focused/Gria2 | RFLPs | Gria2: ↑ R/G site | Suggested as contributor in disease pathogenesis | [29] | |
Human/HPC | Focused/Gria2-4 Grik1-2, KCNA1, 5-HT2C | Sanger sequencing | KCNA1: ↓ I/V site | Inversely associated with disease duration | [30] | |
Mouse/HPC | Transcriptome-wide/whole transcriptome | NGS/Sanger sequencing | 19 DE targets experimentally validated, ↑ Grik2, Ctsb, Rpa, Sparc, Slc1a2, Ovca2, ↓ Ncl, Wipi2, Klhl24, Hspa4l, Slc37a3, Cyfip2 | DE targets involved in disease related pathways | [31] | |
SCZ | Human/PFC | Focused/Gria2 | RFLPs | Gria2: ↓ Q/R site | Possible contributor to disease pathogenesis | [32] |
Human/FC | Focused/5-HT2C | Cloning and Sanger sequencing | 5-HT2C: ↓ site B | ↑ Unedited isoform | [33] | |
Human/PFC | Focused/5-HT2C | Cloning and Sanger sequencing | 5-HT2C: ns site differences | Trend: ↑ unedited isoform | [34] | |
Human/ACC/DLPFC | Transcriptome-wide/whole transcriptome | NGS meta-analysis/independent (validation) cohort in silico analysis | >100 DE sites per region, DE overlap between brain regions (n = 29) | ↑ Global editing, DE targets involved in disease associated pathways | [35] | |
Suicide | Human/PFC | Focused/5-HT2C | Primer extension | 5-HT2C: site A | ↑ Site A | [36] |
Human/PFC | Focused/5-HT2C | Targeted NGS/cloning and Sanger sequencing | 5-HT2C isoforms due to editing | ↑ ABCD isoform (hypoactive) | [37] | |
Human/PFC | Focused/5-HT2C | Targeted NGS/validation cohort analysis | 5-HT2C edited isoforms, ↑ ABCD isoform | ABCD isoform associated with gene expression alterations | [38] | |
Human/ACC/DLPF | Focused/5-HT2C | CE-SSCP | 5-HT2C edited isoforms, ACC: ↑ A, ABDE, ↓ D/DLPFC: ↑ AB | Region-specific differential representation | [39] | |
Depression and suicide | Human/PFC | Focused/5-HT2C | Cloning and Sanger sequencing | 5-HT2C: ↑ site C’ (Ε), ↓ site D | [40] | |
Human/PFC | Focused/5-HT2C | Primer extension and DHPLC/Sanger sequencing | 5-HT2C: sites A and D ns | Trend, Depr.: ↑ D, Suicide: ↑ A | [41] | |
Human/ACC/DLPFC | Focused/PDE8A | CE-SSCP | PDE8A edited isoforms, ACC: ↑ ABCEF, ABC, ABEFG, BFG ↓ B, ABDE/DLPFC: ↑ ABEFG, BCEG, ↓ ABF, BEG | Region specific differential representation | [42] | |
Human/whole blood | Focused/PDE8A | Targeted NGS | PDE8A: ↓ sites B, C, E and D, F ns ↓ Isoforms B, BC, BD, BE, BF | Similar patterns with the brain of suicide decedents | [42] | |
CSDS | Mouse/PFC/BLA | Focused/recoding in neuronal function related transcripts (551 sites) | Targeted NGS (mmPCR_seq) | PFC: ↑ Commd2, Rsad1, Iqgap1, Klf16, Nova1 ↓ Wipi2, Zfp81, Rn45s, Rwdd2b, Dagla, BLA: ↑ Htr2c (C, D site), Gabra3, Tcp11l1, Qpctl ↓ Zfp324, Copa, Gria4, Fubp3, Nova1 | Region-specific DE | [43] |
Autism | Human/CB | Focused/synaptic transcripts (10 targets) | Pyrosequencing/validation: Padlock probes and NGS (5 targets) | Gria 4: ↑ R/G site, Grik2 and 5-HT2C edited isoforms differential representation | Gria4 editing associated with differential splicing isoform usage | [44] |
Human/TC, FC, CB | Transcriptome-wide/whole transcriptome | NGS/2nd cohort meta-analysis/cloning and Sanger sequencing | ↑ Ctsb, Neat1 ↓ Gsk3b, Nova1, Grik1, FAM213A, Dennd3 | ↓ Global editing | [45] |
Disorder | Species/Brain Region | Study Type/Target(s) | Methodology/ Validation Method | DE Targets/Trend Relative to Controls | Remarks | Ref. |
---|---|---|---|---|---|---|
ALS | Human/SC | Focused/Gria2 | RFLPs/Sanger sequencing | Gria2: ↓ Q/R site | [46] | |
Human/neurons $ | Focused/Gria2 | RFLPs | Gria2: ↓ Q/R site | No editing changes in Purkinje cells | [47] | |
Human/SC and motor cortex | Focused/EAAT2 (astroglial glutamate transporter) | Cloning and Sanger sequencing | EAAT2: ↑ intron7 | Alternative polyadenylation and intron 7 retention transcripts (in vitro functional evidence) | [48] | |
Human/SC neurons $ | Focused/Gria2 | RFLPs | Gria2: ↓ Q/R site | [49] | ||
Human/SC | Transcriptome-wide/focus on database listed A-I editing sites | NGS | Gria2: ↓ Q/R site ns trend | Low sample number, n = 5–6/group | [50] | |
ALS (C9orf72) | Human/SC, motor cortex, FC, CB | Transcriptome-wide/whole transcriptome | NGS/ADAR1 and/or ADAR2 deficient hiPSC-MNs cells and cells with aberrant ADAR2 localization | 1526 DE transcripts | No changes in global editing, region-specific hypo- and hyper-edited patterns | [51] |
HD | Human/striatum | Focused/Gria2 | RFLPs | Gria2: ↓ Q/R site | [32] | |
AD | Human/PFC | Focused/Gria2 | RFLPs | Gria2: ↓ Q/R site | [32] | |
Human/HPC | Focused/Gria2 | Sanger sequencing/primer extension | Gria2: ↓ Q/R site | [52] | ||
Human/HPC, temporal and frontal lobe | Focused/recoding in synaptic transcripts (72 targets, 118 sites) | Targeted NGS (mmPCR_seq) | ↓ 5-HT2C receptor isoforms, HPC: ↓ Cacna1d, Ddx58, Fbxl6, Fis1, Flj43663, Gria3, Gria4, Igfbp7, Kcna1, Meg3, Narf, Nova1, Ptpn14, Unc80 ↑ Copa Temporal lobe: ↓ Ccni, Fbxl6, Flj43663, Gria2, Gria4, Grik1, Grik2, Meg3, Mfn1, Tme63b, Unc80 ↑ Narf/Frontal lobe: ↓ Mfn1, Grik2, Meg3, Gria2, Unc80, Ddx58 | ↓ Recoding | [53] | |
Human/HPC | Transcriptome-wide | NGS | 11 DE targets, ↓ Gria2, Gria3, Gria4, Grik1, Grik2 ↑ Blcap, Copa, Vn1r1, Znf235, Znf397, Znf582 | ↓ Recoding | [54] | |
Human/ACC/DLPFC/PCC/aPFC/pSTG/IFGo/FFG/CB/TC | Transcriptome-wide/focus on database listed A-I editing sites | NGS | ↓ Editing in SYT11, MCUR1, SOD2, ORAI2, HSDL2, PFKP, and GPRC5B | DLPFC Samples: ↓ ADAR1 ↑ ADAR3 expression in AD cases | [55] | |
Prion diseases | sCJD and vCJD Rhesus monkeys/CB | Focused/Alu | Cloning and Sanger sequencing | ↓ Alu editing | Strain specific differences | [56] |
sCJD Mouse/Cortex | Transcriptome-wide | NGS and Sanger sequencing | 3 DE targets experimentally validated, Mouse pre-clinical: ↓ Sidt2, ↑ Fkrp/Mouse clinical: ↑ Rragd | ↓ Global editing, Human cross-validation: ↓ Paqr8, ↑ Ctss, Rrgad | [57] |
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Karagianni, K.; Pettas, S.; Christoforidou, G.; Kanata, E.; Bekas, N.; Xanthopoulos, K.; Dafou, D.; Sklaviadis, T. A Systematic Review of Common and Brain-Disease-Specific RNA Editing Alterations Providing Novel Insights into Neurological and Neurodegenerative Disease Manifestations. Biomolecules 2022, 12, 465. https://doi.org/10.3390/biom12030465
Karagianni K, Pettas S, Christoforidou G, Kanata E, Bekas N, Xanthopoulos K, Dafou D, Sklaviadis T. A Systematic Review of Common and Brain-Disease-Specific RNA Editing Alterations Providing Novel Insights into Neurological and Neurodegenerative Disease Manifestations. Biomolecules. 2022; 12(3):465. https://doi.org/10.3390/biom12030465
Chicago/Turabian StyleKaragianni, Korina, Spyros Pettas, Georgia Christoforidou, Eirini Kanata, Nikolaos Bekas, Konstantinos Xanthopoulos, Dimitra Dafou, and Theodoros Sklaviadis. 2022. "A Systematic Review of Common and Brain-Disease-Specific RNA Editing Alterations Providing Novel Insights into Neurological and Neurodegenerative Disease Manifestations" Biomolecules 12, no. 3: 465. https://doi.org/10.3390/biom12030465
APA StyleKaragianni, K., Pettas, S., Christoforidou, G., Kanata, E., Bekas, N., Xanthopoulos, K., Dafou, D., & Sklaviadis, T. (2022). A Systematic Review of Common and Brain-Disease-Specific RNA Editing Alterations Providing Novel Insights into Neurological and Neurodegenerative Disease Manifestations. Biomolecules, 12(3), 465. https://doi.org/10.3390/biom12030465