The DOI matches its Crossref record; 43 of the 43 references it cites were found in a registry or an index; 2 of the 23 sources its claims cite were checked for support.
RNA binding protein AUF1/HNRNPD regulates nuclear export, stability and translation of SNCA transcripts
Open accessAbstract
Alpha-synuclein (SNCA) accumulation plays a central role in the pathogenesis of Parkinson's disease. Determining and interfering with the mechanisms that control SNCA expression is one approach to limiting disease progression. Currently, most of our understanding of SNCA regulation is protein-based. Post-transcriptional mechanisms directly regulating SNCA mRNA expression via its 3′ untranslated region (3′UTR) were investigated here. Mass spectrometry of proteins pulled down from murine brain lysates using a biotinylated SNCA 3′UTR revealed multiple RNA-binding proteins, of which HNRNPD/AUF1 was chosen for further analysis. AUF1 bound both proximal and distal regions of the SNCA 3′UTR, but not the 5′UTR or CDS. In the nucleus, AUF1 attenuated SNCA pre-mRNA maturation and was indispensable for the export of SNCA transcripts. AUF1 destabilized SNCA transcripts in the cytosol, primarily those with shorter 3′UTRs, independently of microRNAs by recruiting the CNOT1-CNOT7 deadenylase complex to trim the polyA tail. Furthermore, AUF1 inhibited SNCA mRNA binding to ribosomes. These data identify AUF1 as a multi-tasking protein regulating maturation, nucleocytoplasmic shuttling, stability and translation of SNCA transcripts.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
AUF1/HNRNPD binds the U-rich SNCA 3′UTR and regulates SNCA expression at multiple post-transcriptional steps: it attenuates pre-mRNA maturation, is required for nuclear export, recruits CNOT1-CNOT7 to deadenylate and destabilize shorter SNCA transcripts, and blocks ribosomal engagement. The net effect is that both AUF1 excess and AUF1 depletion lower SNCA protein, indicating AUF1 levels and localization must be balanced for normal SNCA expression.
Key findings
- Biotinylated 2529 nt SNCA 3′UTR pull-down from postnatal day 3 mouse brain lysates identified 133 unique proteins after subtracting 559 streptavidin-bound proteins from 404 pulled proteins; enriched functions included RNA binding (E/R 4.8, FDR 1.3 × 10−8), mRNA binding (E/R 9.5, FDR 4.5 × 10−6), and mRNA 3′UTR binding (E/R 15, FDR 1.8 × 10−3). AUF1 was selected for follow-up.
- AUF1 associated with SNCA mRNA: RIP showed SNCA mRNA was eightfold enriched in anti-AUF1 IP versus IgG, and AUF1 bound exclusively to the SNCA 3′UTR in both proximal and distal portions, with more AUF1 species binding the distal portion.
- AUF1 overexpression reduced total SNCA mRNA by approximately 18% (p < 0.01) in SK-N-SH and HEK293A cells; the long SNCA transcript did not significantly change in SK-N-SH but decreased by 7% (p < 0.05) in HEK293A. AUF1 silencing increased total SNCA transcript levels by 45% (p < 0.05) in SK-N-SH and 14% (p < 0.05) in HEK293A, and increased long SNCA transcript levels by 34% (p < 0.05) and 24% (p < 0.05), respectively. AUF1 silencing increased total SNCA mRNA stability by nearly 40% (p < 0.01) but did not significantly affect long-transcript stability.
- AUF1 overexpression shifted SNCA RT-qPCR products toward higher melting temperature, indicating shorter polyA tails, while AUF1 silencing shifted them toward lower melting temperature, indicating longer polyA tails. AUF1 increased CNOT1 association with SNCA 3′UTR; CNOT1 immunoprecipitated AUF1 (1.6-fold enrichment) and CNOT7 (3-fold enrichment), but not CNOT6. miR-7 and miR-153 expression were unaffected by AUF1 levels, and AUF1 overexpression did not affect miR-7/153-mediated SNCA degradation.
- AUF1 overexpression decreased SNCA protein by 35% (p < 0.001) in SK-N-SH and 33% (p < 0.01) in HEK293 cells, reduced total SNCA transcript association with ribosomes by 35% (p < 0.05) and long-transcript association by 49% (p < 0.05), without affecting 5S, ACTB, or GAPDH ribosome association or global translation. AUF1 silencing decreased SNCA protein by 33% (p < 0.001) in SK-N-SH and 20% (p < 0.01) in HEK293 cells, while not significantly affecting SNCA transcript-ribosome association.
- AUF1 silencing increased mature exonic SNCA mRNA in the nucleus by 21% (p < 0.01), indicating interference with pre-mRNA maturation, and decreased nuclear export of total and long 3′UTR SNCA transcripts by 130% (p < 0.05) and 250% (p < 0.05), respectively. AUF1 overexpression did not significantly affect maturation or nuclear export.
Methods
- Proteomics: biotinylated RNA spanning the 2529 nt SNCA 3′UTR was incubated with total brain lysates from postnatal day 3 mouse brains, pulled down with streptavidin beads, and analyzed by nano LC-MS/MS; Gene Ontology analysis used WebGestalt 2019.
- Cell work: human neuroblastoma SK-N-SH and embryonic adrenal precursor HEK293A cells were transfected with AUF1 overexpression or shRNA plasmids for 48 h. Assays included RT-qPCR, RNA immunoprecipitation, actinomycin D mRNA half-life measurement, ePAT polyA tail analysis, nucleocytosolic fractionation, RPL22 RiboTag ribosome association, co-immunoprecipitation, Western blotting, and SUnSET global translation measurement.
- Statistics: data from at least three independent biological replicates, presented as mean ± SD; two-tailed Student’s t-test for paired samples, one-way ANOVA with Dunnett’s post hoc for multiple comparisons, p < 0.05 considered significant.
Limitations
- The paper does not state limitations in a dedicated section.
- Evident from the text: the mechanistic work is largely in SK-N-SH and HEK293A cell lines, with the initial proteomic screen using postnatal day 3 mouse brain lysates rather than human brain or Parkinson’s disease tissue; no in vivo disease model or human validation is reported.
- Evident from the text: several effects are modest or statistically insignificant, including AUF1 overexpression effects on the long SNCA transcript in SK-N-SH cells, miR-7/153 effects after AUF1 silencing (p = 0.12 for total and p = 0.18 for long SNCA mRNA), and AUF1 overexpression effects on nuclear export (p = 0.95 and p = 0.92).
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
2 of 23 cited sources checked · 1 supported · 0 flagged · accuracy not yet measured
- Findingown data
AUF1 overexpression does not affect miR-7/153-mediated SNCA mRNA degradation.
“AUF1 overexpression did not affect miR-7/153-mediated SNCA mRNA degradation (figure 3e,f).”
Quote in the paperSubstantial claim - Findingown data
AUF1 does not significantly affect the stability of the SNCA transcript with the long 3′UTR.
“AUF1 did not significantly affect the stability of the SNCA transcript with the long 3′UTR (figure 2i,j).”
Quote in the paperSubstantial claim - Findingown data
AUF1 overexpression does not generally affect global translation rates in SK-N-SH cells.
“measuring global protein synthesis rates using the non-isotopic SUnSET method [24] revealed that AUF1 overexpression does not generally affect translation in SK-N-SH cells”
Quote in the paperSubstantial claim - Findingown data
AUF1 overexpression marginally decreases total SNCA mRNA half-life.
“AUF1 overexpression marginally decreased total SNCA mRNA half-life”
Quote in the paperSubstantial claim - Findingown data
After filtering out proteins bound to streptavidin beads alone, 133 unique proteins remained associated with the biotinylated SNCA 3′UTR in mouse brain lysate.
“After filtering out the latter dataset for non-specific labelling by deducting proteins bound to streptavidin beads alone, 133 unique proteins remained (figure 1a).”
Quote in the paperSubstantial claim
- Findingown data
CNOT7 is not pulled down on the SNCA 3′UTR in the same assay.
“This association was unaccompanied by a catalytic CNOT7 pull-down on SNCA 3′UTR”
Quote in the paperNot a substantial claim - Findingown data
AUF1 overexpression does not affect ribosomal association of control mRNAs 5S, ACTB, and GAPDH in SK-N-SH cells.
“The association of three control mRNAs, 5S, ACTB and GAPDH, with the ribosomes was unaffected by AUF1 overexpression”
Quote in the paperSubstantial claim - Findingown data
AUF1 expression levels do not affect mature miR-7 or miR-153 expression in SK-N-SH cells.
“Figure 3c,d show that neither mature miR-7 nor miR-153 expression was affected by AUF1 levels.”
Quote in the paperSubstantial claim - Findingown data
Increasing the quantity of AUF1 in SK-N-SH lysates increases the association of CNOT1 with the SNCA 3′UTR.
“Figure 3h shows that, by increasing the quantity of AUF1 available in lysates, there was an increased association of CNOT1 with SNCA 3′UTR.”
Quote in the paperSubstantial claim - Findingown data
SNCA 3′UTR-bound proteins from mouse brain lysate are enriched for RNA binding, mRNA binding, and mRNA 3′UTR binding molecular functions.
“SNCA 3′UTR-bound proteins displayed predominantly ‘RNA binding’ (E/R 4.8, FDR 1.3 × 10−8), ‘mRNA binding’ (E/R 9.5, FDR 4.5 × 10−6) and ‘mRNA 3′UTR binding’ (E/R 15, FDR 1.8 × 10−3) activities (figure 1b).”
Quote in the paperSubstantial claim - Findingown data
In the actinomycin D stability assay, AUF1 silencing increased total SNCA mRNA levels by nearly 40% (p < 0.01).
“AUF1 silencing increased total SNCA mRNA expression by nearly 40% (p < 0.01).”
Quote in the paperSubstantial claim - Findingown data
AUF1 overexpression for 48 h reduces steady-state total endogenous SNCA mRNA levels by approximately 18% (p < 0.01) in both SK-N-SH and HEK293A cells.
“Plasmid-mediated overexpression of AUF1 in SK-N-SH and HEK293A cells for 48 h, followed by RT-qPCR analysis of RNA extracts, reduced steady-state total levels of endogenous SNCA mRNA by approximately 18% (p < 0.01) in both cell lines.”
Quote in the paperSubstantial claim - Findingown data
The top enriched biological processes among SNCA 3′UTR-bound proteins are regulation of mRNA metabolic process, mRNA metabolic process, and regulation of mRNA processing.
“The top three biological processes that were enriched were ‘regulation of mRNA metabolic process' (E/R 12, FDR 2.9 × 10−9), ‘mRNA metabolic process’ (E/R 6.2, FDR 7.1 × 10−8) and ‘regulation of mRNA processing’ (E/R 15.1, FDR 7.1 × 10−8) (figure 1c).”
Quote in the paperNot a substantial claim - Findingown data
Endogenous AUF1 associates with SNCA mRNA in SK-N-SH cells, as shown by eight-fold enrichment of SNCA mRNA in AUF1 immunoprecipitation compared with control IgG.
“Figure 1d shows that SNCA mRNA was eight-fold enriched in AUF1 IP compared with control IgG IP, confirming that it is part of the AUF1 RNP complexes.”
Quote in the paperSubstantial claim - Findingown data
AUF1 depletion does not significantly affect SNCA transcript association with ribosomes.
“Further, AUF1 depletion did not significantly affect SNCA transcript association with the ribosomes (figure 4e).”
Quote in the paperSubstantial claim - Findingown data
This study identified RBPs that bound SNCA 3′UTR.
“In conclusion, this study identified RBPs that bound SNCA 3′UTR and detailed the complex interaction outcomes between AUF1 and SNCA mRNA.”
Quote in the paperSubstantial claim - Findingown data
AUF1 silencing increases mature (exonic) SNCA mRNA levels in the nucleus by 21% (p < 0.01).
“By contrast, AUF1 silencing increased by 21% (p < 0.01) mature (exonic) SNCA mRNA levels in the nucleus (figure 5b)”
Quote in the paperSubstantial claim - Findingreasoning
The protein lists from this study and Marchese et al. overlapped on only three proteins: Sub1/TCP4, HNRNPA1/ROA1, and ELAVL1/ELAV1.
“The protein lists from these two studies only overlapped on three proteins, Sub1/TCP4, HNRNPA1/ROA1, and ELAVL1/ELAV1, reflecting the different experimental approaches used.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Marchese D et al. 2017 Discovering the 3′ UTR-mediated regulation of alpha-synuclein. Nucleic Acids Res. 45, 12 888- 12 903. (10.1093/nar/gkx1048) PMC5728410 29149290 source
- Findingown data
AUF1 overexpression does not significantly affect maturation of SNCA pre-mRNAs.
“and did not significantly affect the maturation of SNCA pre-mRNAs (figure 5b).”
Quote in the paperSubstantial claim - Study design and conductown data
The pull-down protocol used here is valid for discovering 3′UTR interactors en masse.
“These results validate the particular protocol for discovering 3′UTR interactors en masse”
Quote in the paperSubstantial claim - Interpretationown data
The effect of AUF1 on ribosomal association is specific to SNCA mRNAs.
“indicating that the effect of AUF1 was specific to SNCA mRNAs (figure 4b).”
Quote in the paperSubstantial claim - Interpretationreasoning
The diminished effect of AUF1 on the long SNCA transcript is likely due to interference from additional RBPs bound on the distal segment of the SNCA 3′UTR.
“This effect is diminished on the long SNCA transcript, likely due to the interference from additional RBPs bound on the distal segment of SNCA 3′UTR.”
Quote in the paperSubstantial claim - Interpretationown data
SNCA 3′UTR interacting proteins are implicated in mRNA metabolism.
“indicate that SNCA 3′UTR interacting proteins are implicated in mRNA metabolism.”
Quote in the paperSubstantial claim - Interpretationown data
AUF1 downregulates SNCA mRNA levels by destabilizing SNCA mRNA via deadenylation.
“These findings suggest that AUF1 downregulates SNCA mRNA levels by destabilizing SNCA mRNA via deadenylation.”
Quote in the paperSubstantial claim - Interpretationnone given
AUF1 is essential for the nuclear export of mature SNCA transcripts.
“In the nucleus, AUF1 interferes with SNCA pre-mRNA maturation and is essential for the nuclear export of mature transcripts.”
Quote in the paperSubstantial claim - Interpretationreasoning
AUF1 deadenylates and destabilizes SNCA transcripts with shorter 3′UTR.
“In the cytoplasm, AUF1 recruits the CNOT1-CNOT7 complex, deadenylating and destabilizing SNCA transcripts with shorter 3′UTR.”
Quote in the paperSubstantial claim - Interpretationnone given
AUF1 inhibits the association of SNCA transcripts with the ribosomes.
“Moreover, AUF1 inhibits the association of SNCA transcripts with the ribosomes, attenuating SNCA protein expression.”
Quote in the paperSubstantial claim - Interpretationreasoning
AUF1 attenuates SNCA protein expression.
“Moreover, AUF1 inhibits the association of SNCA transcripts with the ribosomes, attenuating SNCA protein expression.”
Quote in the paperSubstantial claim - Interpretationown data
AUF1 interferes with SNCA transcript maturation.
“indicating that AUF1 interferes with SNCA transcripts maturation.”
Quote in the paperSubstantial claim - Interpretationnone given
In the cytoplasm, AUF1 recruits the CNOT1-CNOT7 complex.
“In the cytoplasm, AUF1 recruits the CNOT1-CNOT7 complex, deadenylating and destabilizing SNCA transcripts with shorter 3′UTR.”
Quote in the paperSubstantial claim - Interpretationnone given
AUF1 interferes with SNCA pre-mRNA maturation in the nucleus.
“In the nucleus, AUF1 interferes with SNCA pre-mRNA maturation and is essential for the nuclear export of mature transcripts.”
Quote in the paperSubstantial claim
- It may state two separate claims as one. 32
- Probably not a substantial claim. 18
- The quote only partly states this claim. 1
It may state two separate claims as one.
PremisecitationMetformin induces nuclear retention of AUF1, disrupting its interaction with target mRNAs, and is neuroprotective in different Parkinson's disease models in part by decreasing SNCA levels, phosphorylation, and aggregation.
“Coincidentally, the hypoglycemic agent metformin that induces nuclear retention of AUF1 disrupting its interaction with target mRNAs [31], is neuroprotective in different PD models in part by decreasing SNCA levels [32], phosphorylation [33,34] and aggregation [35].”
Quote in the paperNot a substantial claim2 of 4 sources checked- cites [31] Noren Hooten N et al. 2016 Metformin-mediated increase in DICER1 regulates microRNA expression and cellular senescence. Aging Cell 15, 572- 581. (10.1111/acel.12469) 26990999 PMC4854919 source
- cites [32] Hussein AM, Eldosoky M, El-Shafey M, El-Mesery M, Ali AN, Abbas KM, Abulseoud OA. 2019 Effects of metformin on apoptosis and alpha-synuclein in a rat model of pentylenetetrazole-induced epilepsy. Can. J. Physiol. Pharmacol. 97, 37- 46. (10.1139/cjpp-2018-0266) 30308130 source
- cites [33] Katila N, Bhurtel S, Shadfar S, Srivastav S, Neupane S, Ojha U, Jeong GS, Choi DY. 2017 Metformin lowers alpha-synuclein phosphorylation and upregulates neurotrophic factor in the MPTP mouse model of Parkinson's disease. Neuropharmacology 125, 396- 407. (10.1016/j.neuropharm.2017.08.015) 28807678 source
- cites [34] Perez-Revuelta BI, Hettich MM, Ciociaro A, Rotermund C, Kahle PJ, Krauss S, Di Monte DA. 2014 Metformin lowers Ser-129 phosphorylated alpha-synuclein levels via mTOR-dependent protein phosphatase 2A activation. Cell Death Dis. 5, e1209. (10.1038/cddis.2014.175) 24810045 PMC4047877 source
The Abstract reports that metformin lowers phosphorylated Ser129 α-synuclein in cultured cells and the brains of wild-type mice, supporting the phosphorylation part attached to this citation. The Discussion describes neuroprotection in a Parkinson’s disease model for a different agent, EHT; this paper does not establish that metformin is neuroprotective in different PD models or that reduced phosphorylation causes such protection. The AUF1, SNCA-level, and aggregation claims have separate citations in the citing sentence. (LLM, conf=0.88)
Experimental — accuracy not yet measured
It may state two separate claims as one.
Findingown dataAUF1 overexpression shifts SNCA RT-qPCR products toward higher melting temperature, indicating shorter polyA tails, while AUF1 silencing shifts them toward lower melting temperature, indicating longer polyA tails.
“AUF1 overexpression shifted PCR products toward higher Tm, indicative of shorter polyA, while AUF1 silencing shifted PCR products toward lower Tm, indicative of longer polyA.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataAUF1 binds exclusively to the SNCA 3′UTR, in both proximal and distal portions, with more AUF1 species binding the distal portion.
“Western blotting revealed that AUF1 bound exclusively to the SNCA 3′UTR in both proximal and distal portions, with a greater number of AUF1 species binding the latter”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataAUF1 overexpression does not significantly change the long SNCA transcript in SK-N-SH cells but decreases it by 7% (p < 0.05) in HEK293A cells.
“The expression of the SNCA transcript with the 2529 nucleotides 3′UTR (hereafter called ‘long transcript’) did not significantly change in SK-N-SH cells but decreased by 7% (p < 0.05) in HEK293A cells (figure 2a–c).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataSilencing AUF1 with two different shRNA plasmids for 48 h increases total SNCA transcript levels by 45% (p < 0.05) in SK-N-SH and 14% (p < 0.05) in HEK293A cells.
“silencing AUF1 expression by overexpressing two different AUF1 shRNA plasmids for 48 h increased total SNCA transcript levels by 45% (p < 0.05) in SK-N-SH and 14% (p < 0.05) in HEK293A”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataCNOT1 shows no interaction with CNOT6 and appears to bind PABPC1.
“However, CNOT1 showed no interaction with CNOT6, and there appeared to be binding to PABPC1”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataAUF1 overexpression reduces association of total SNCA transcripts with ribosomes by 35% (p < 0.05) and of long 3′UTR SNCA transcripts by 49% (p < 0.05) in SK-N-SH cells.
“RPL22-IP with anti-flag beads followed by real-time RT-PCR to monitor SNCA mRNA levels revealed a 35% (p < 0.05) reduction in the association of total SNCA transcripts with the ribosomes following AUF1 overexpression. Similarly, the levels of the SNCA transcript with the long 3′UTR were reduced by 49% (p < 0.05).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataAUF1 overexpression for 48 h decreases total SNCA protein levels by 35% (p < 0.001) in SK-N-SH and 33% (p < 0.01) in HEK293 cells.
“Western blotting of total protein extracts from AUF1 overexpressing SK-N-SH and HEK293 cells revealed a 35% (p < 0.001) and 33% (p < 0.01) decrease in total SNCA protein levels after 48 h, respectively (figure 4a).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataAUF1 silencing increases long SNCA transcript levels by 34% (p < 0.05) in SK-N-SH cells and by 24% (p < 0.05) in HEK293A cells.
“while the long SNCA transcript levels increased by 34% (p < 0.05) in SK-N-SH cells and by 24% (p < 0.05) in HEK293A cells (figure 2d–f).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataAUF1 silencing decreases the effect of miR-7/153 on total and long SNCA mRNA levels by 22% and 28%, respectively, but these changes are statistically insignificant (p = 0.12 and p = 0.18).
“AUF1 silencing decreased by 22% and 28% the effect of miR-7/153 on total and long SNCA mRNA levels, yet these results were statistically insignificant (p = 0.12 for total and p = 0.18 for long SNCA mRNA).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataCNOT1 immunoprecipitates with AUF1 (1.6-fold enrichment) and with CNOT7 (3-fold enrichment) in SK-N-SH cells.
“CNOT1 immunoprecipitated with AUF1 (1.6-fold enrichment), confirming the above pull-down data, and with CNOT7 (3-fold enrichment), validating previous studies [21,22].”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataAUF1 overexpression decreases the exon-to-intron ratio of SNCA transcripts in total cell lysates but not in nuclear extracts.
“AUF1 overexpression decreased the exon-to-intron ratio of SNCA transcripts in total cell lysates but not in nuclear extracts”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataAUF1 depletion decreases nuclear export of total and long 3′UTR SNCA transcripts by 130% (p < 0.05) and 250% (p < 0.05), respectively.
“AUF1 depletion decreased their nuclear export by 130% (p < 0.05) and 250% (p < 0.05), respectively (figure 5e,f).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Findingown dataAUF1 overexpression marginally increases nuclear export of total (13%, p = 0.95) and long (29%, p = 0.92) 3′UTR SNCA transcripts, but these changes are not statistically significant.
“whereas AUF1 overexpression marginally increased the nuclear export of total (13%, p = 0.95) and long (29%, p = 0.92) 3′UTR SNCA transcripts (figure 5c,d)”
Quote in the paperNot a substantial claimProbably not a substantial claim. It may be too vague to check against evidence.
Findingown dataThis study detailed the complex interaction outcomes between AUF1 and SNCA mRNA.
“In conclusion, this study identified RBPs that bound SNCA 3′UTR and detailed the complex interaction outcomes between AUF1 and SNCA mRNA.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataAUF1 silencing for 48 h decreases total SNCA protein levels by 33% (p < 0.001) in SK-N-SH and 20% (p < 0.01) in HEK293 cells.
“Western blotting of total protein extracts from SK-N-SH and HEK293 cells after AUF1 silencing for 48 h revealed a 33% (p < 0.001) and 20% (p < 0.01) decrease in total SNCA protein levels, respectively (figure 4d).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
InterpretationcitationAUF1 mediates deadenylation of SNCA mRNA by directly recruiting the CNOT1-CNOT7 complex to the SNCA 3′UTR and not through the miR7/153-GW182-CNOT1 pathway.
“These findings indicate that AUF1 mediates the deadenylation of SNCA mRNA by directly recruiting the CNOT1-CNOT7 complex to SNCA 3′UTR and not through the miR7/153-GW182-CNOT1 pathway [23].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [23] Fabian MR et al. 2011 miRNA-mediated deadenylation is orchestrated by GW182 through two conserved motifs that interact with CCR4-NOT. Nat. Struct. Mol. Biol. 18, 1211- 1217. (10.1038/nsmb.2149) 21984185 source
- The authors state this as an assumption: The pull-down assay does not favour third-order interactions, so failure to detect CNOT7 on SNCA 3′UTR does not indicate absence of CNOT7 in the complex.
It may state two separate claims as one.
Interpretationown dataExcess AUF1 attenuates SNCA protein levels by two alternative mechanisms: destabilizing shorter SNCA transcripts and blocking translation of all SNCA transcripts.
“Overall, these findings suggest that excess AUF1 attenuates SNCA protein levels by two alternative mechanisms: (i) destabilizing shorter SNCA transcripts and (ii) blocking the translation of all SNCA transcripts.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataAUF1 appears generally dispensable for miR-7/153 function on SNCA mRNA, although in the absence of AUF1 miR-7/153 may be less efficient in lowering SNCA levels.
“These findings suggest that, in the absence of AUF1, miR-7/153 may not be as efficient in lowering SNCA levels, but AUF1 appears to be generally dispensable for their function on SNCA mRNA.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataAUF1 destabilizes mostly SNCA transcripts with shorter 3′UTRs, resulting in downregulation of total SNCA mRNA levels.
“Overall, this set of experiments demonstrates that AUF1 destabilizes mostly the SNCA transcripts with the shorter 3′UTRs, resulting in significant downregulation of total SNCA mRNA levels.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataUnder physiological conditions, the levels and subcellular localization of AUF1 maintain optimum expression of SNCA, and conditions that alter AUF1 binding or distribution will profoundly affect SNCA expression.
“These data suggest that, under physiological conditions, the levels and subcellular localization of AUF1 maintain optimum expression of SNCA and that conditions that alter AUF1 binding or distribution will profoundly affect SNCA expression”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationPoint mutations, gene duplications, and gene triplications at the SNCA locus occur in several families with autosomal dominant early-onset Parkinson's disease.
“Several families with autosomal dominant early-onset PD have had point mutations, gene duplications, and gene triplications at the SNCA locus [1–3].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [1] Chartier-Harlin MC et al. 2004 α-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364, 1167- 1169. (10.1016/S0140-6736(04)17103-1) 15451224 source
- cites [2] Polymeropoulos MH et al. 1997 Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276, 2045- 2047. (10.1126/science.276.5321.2045) 9197268 source
- cites [3] Singleton AB et al. 2003 α-Synuclein locus triplication causes Parkinson's disease. Science 302, 841. (10.1126/science.1090278) 14593171 source
It may state two separate claims as one.
InterpretationreasoningToo little nuclear AUF1 will diminish SNCA mRNA nucleocytoplasmic shuttling, and too much cytosolic AUF1 will destabilize mRNA and block translation.
“too little nuclear AUF1 will diminish SNCA mRNA nucleocytoplasmic shuttling, too much cytosolic AUF1 will destabilize mRNA and block translation.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationIn the cytoplasm, AUF1 binds U-, GU- and UG-rich sequences and either promotes decay or enhances stability and translation of target mRNAs by poorly understood mechanisms.
“In the cytoplasm, it binds U-, GU- and UG-rich sequences and either promotes decay or enhances the stability and translation of target mRNAs by mechanisms that are still poorly understood [14].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14] Yoon JH et al. 2014 PAR-CLIP analysis uncovers AUF1 impact on target RNA fate and genome integrity. Nat. Commun. 5, 5248. (10.1038/ncomms6248) 25366541 PMC4291169 source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationELAVL1 binds the SNCA 3′UTR, and AUF1 competes with HuR for binding to specific U/AU-rich motifs in other mRNA targets.
“given that ELAVL1 binds SNCA 3′UTR [30] and AUF1 has been shown to compete with HuR for binding to specific U/AU-rich motifs in other mRNA targets [36,37]”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [30] Marchese D et al. 2017 Discovering the 3′ UTR-mediated regulation of alpha-synuclein. Nucleic Acids Res. 45, 12 888- 12 903. (10.1093/nar/gkx1048) PMC5728410 29149290 source
- cites [36] Fotinos A, Fritz DT, Lisica S, Liu Y, Rogers MB. 2016 Competing repressive factors control bone morphogenetic protein 2 (BMP2) in mesenchymal cells. J. Cell. Biochem. 117, 439- 447. (10.1002/jcb.25290) 26212702 PMC4913784 source
- cites [37] Sun S, Zhang X, Lyu L, Li X, Yao S, Zhang J. 2016 Autotaxin expression is regulated at the post-transcriptional level by the RNA-binding proteins HuR and AUF1. J. Biol. Chem. 291, 25 823- 25 836. (10.1074/jbc.M116.756908) PMC5207058 27784781 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationViral-mediated overexpression of wild-type or mutant SNCA in nigral neurons of rodents and non-human primates produces progressive motor dysfunction resembling Parkinson's disease motor symptoms.
“Viral-mediated overexpression of wild-type or mutant SNCA within nigral neurons of rodents and non-human primates resulted in progressive motor dysfunction resembling the motor symptoms of PD patients [4–6].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [4] Kirik D, Rosenblad C, Burger C, Lundberg C, Johansen TE, Muzyczka N, Mandel RJ, Bjorklund A. 2002 Parkinson-like neurodegeneration induced by targeted overexpression of alpha-synuclein in the nigrostriatal system. J. Neurosci. 22, 2780- 2791. (10.1523/JNEUROSCI.22-07-02780.2002) 11923443 PMC6758323 source
- cites [5] Bianco L, Ridet C, Schneider JL, Deglon BL, Aebischer N. 2002 α-synucleinopathy and selective dopaminergic neuron loss in a rat lentiviral-based model of Parkinson's disease. Proc. Natl Acad. Sci. USA 99, 10 813- 10 818. (10.1073/pnas.152339799) 12122208 PMC125054 source
- cites [6] Oliveras-Salva M, Van der Perren A, Casadei N, Stroobants S, Nuber S, D'Hooge R, Van den Haute C, Baekelandt V. 2013 rAAV2/7 vector-mediated overexpression of alpha-synuclein in mouse substantia nigra induces protein aggregation and progressive dose-dependent neurodegeneration. Mol. Neurodegeneration 8, 44. (10.1186/1750-1326-8-44) PMC4222878 24267638 source
It may state two separate claims as one.
Interpretationown dataAUF1 depletion promotes SNCA pre-mRNA maturation but impairs nuclear export of mature transcripts, thereby impacting mRNA translation and total protein levels.
“Collectively, AUF1 depletion promotes SNCA pre-mRNA maturation but impairs the nuclear export of mature transcripts, thereby impacting mRNA translation and total protein levels.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductnone givenEach qPCR run included reverse-transcription-negative controls, and each sample was tested in triplicate.
“Each qPCR run included reverse-transcription-negative controls, and each sample was tested in triplicate.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationThe more extended SNCA transcript variant shows similar expression to shorter transcripts and has been linked to Parkinson's disease pathology.
“The more extended transcript variant shows a similar expression to shorter transcripts and has been linked to PD pathology [16].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Rhinn H, Qiang L, Yamashita T, Rhee D, Zolin A, Vanti W, Abeliovich A. 2012 Alternative alpha-synuclein transcript usage as a convergent mechanism in Parkinson's disease pathology. Nat. Commun. 3, 1084. (10.1038/ncomms2032) 23011138 PMC3660047 source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationAUF1 pre-mRNA alternative splicing generates four protein isoforms (p37, p40, p42, p45) that shuttle between nucleus and cytoplasm and may exhibit differential affinity for target transcripts.
“AUF1 pre-mRNA alternative splicing generates four protein isoforms (p37, p40, p42 and p45) that shuttle between the nucleus and cytoplasm and may exhibit differential affinity for target transcripts [13].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] White EJ, Matsangos AE, Wilson GM. 2017 AUF1 regulation of coding and noncoding RNA. Wiley Interdiscipl. Rev. 8, e1393. (10.1002/wrna.1393) PMC5315606 27620010
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationMarchese et al. identified 27 top RBPs binding SNCA mRNA by in vitro protein library screening, prioritized ELAVL1 and TIAR, and showed TIAR positively regulates SNCA mRNA translation.
“To identify RBPs that bind SNCA mRNA, Marchese et al. first reported an in vitro protein library screening, identifying 27 top interactors. They prioritized focus on two RBPs, ELAVL1 and TIAR, and showed that TIAR, in particular, positively regulated SNCA mRNA translation [30].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Marchese D et al. 2017 Discovering the 3′ UTR-mediated regulation of alpha-synuclein. Nucleic Acids Res. 45, 12 888- 12 903. (10.1093/nar/gkx1048) PMC5728410 29149290 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataThe A260/280 ratio of all samples was greater than 1.9.
“The A260/280 ratio of all samples was greater than 1.9.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductown dataAn alternative shRNA plasmid targeting all AUF1 transcripts was used as an alternative to the authors' shRNAs, and there was no difference in results.
“An alternative shRNA plasmid targeting all AUF1 transcripts was kindly provided by Dr M. Gorospe and was used as an alternative to our shRNAs [38]; there was no difference in results.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38] Lal A, Mazan-Mamczarz K, Kawai T, Yang X, Martindale JL, Gorospe M. 2004 Concurrent versus individual binding of HuR and AUF1 to common labile target mRNAs. EMBO J. 23, 3092- 3102. (10.1038/sj.emboj.7600305) 15257295 PMC514922 source
Probably not a substantial claim. The quote only partly states this claim.
Study design and conductown dataData in figures 2, 4, and 5 show the mean ± s.d. from at least 3 biological replicates.
“Data show the mean ± s.d. from at least 3 biological replicates (*p < 0.05, **p < 0.01, ***p < 0.001).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataSanger sequencing verified the DNA sequence of all constructs.
“Sanger sequencing verified the DNA sequence of all constructs at CeMIA SA (Larisa, Greece).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
PremisecitationmRNAs of presynaptic genes, like SNCA, display significantly longer 3′UTRs than all other cellular transcripts, indicating they are biased toward post-transcriptional regulation.
“Further, the mRNAs of presynaptic genes, like SNCA, display significantly longer 3′UTRs than all other cellular transcripts, indicating that they are biased toward post-transcriptional regulation of expression [17].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Paschou M, Paraskevopoulou MD, Vlachos IS, Koukouraki P, Hatzigeorgiou AG, Doxakis E. 2012 miRNA regulons associated with synaptic function. PLoS ONE 7, e46189. (10.1371/journal.pone.0046189) 23071543 PMC3468272 source
Probably not a substantial claim.
Study design and conductown dataThe data were compiled and analysed from at least three independent biological replicates.
“The data were compiled and analysed from at least three independent biological replicates and are presented as the mean ± standard deviation (SD).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataEmGFP plasmid transfection indicated that efficiency was approximately 80% for both cell lines at 48 h.
“EmGFP plasmid transfection indicated that efficiency was approximately 80% for both cell lines at 48 h.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationSNCA is a major component of Lewy bodies in sporadic Parkinson's disease and dementia with Lewy bodies and of glial and neuronal inclusions in multiple system atrophy.
“Moreover, SNCA is a major component of neuronal cytoplasmic deposits known as Lewy bodies (LB) in sporadic PD and dementia with Lewy bodies (DLB) and other proteinaceous inclusions in both glial and neuronal cells in multiple system atrophy (MSA) [7].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M. 1998 α-synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies. Proc. Natl Acad. Sci. USA 95, 6469- 6473. (10.1073/pnas.95.11.6469) 9600990 PMC27806 source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationAUF1 deficiency accelerates ageing in mice and increases senescence in mouse and human cells.
“AUF1 deficiency accelerates ageing in mice and increases senescence in both mouse and human cells [15].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] Pont AR, Sadri N, Hsiao SJ, Smith S, Schneider RJ. 2012 mRNA decay factor AUF1 maintains normal aging, telomere maintenance, and suppression of senescence by activation of telomerase transcription. Mol. Cell 47, 5- 15. (10.1016/j.molcel.2012.04.019) 22633954 PMC3966316 source
The paper relies on this without support.
The SNCA mRNA has a highly conserved U-rich 3′UTR of about 575 nucleotides that is alternatively polyadenylated in humans to produce a 2,529 nt transcript.
“The SNCA mRNA possesses a highly conserved and U-rich 3′UTR of about 575 nucleotides (nt) that is alternatively polyadenylated in humans to produce a transcript of 2.529 nt.”
The authors state this as an assumption.
The pull-down assay does not favour third-order interactions, so failure to detect CNOT7 on SNCA 3′UTR does not indicate absence of CNOT7 in the complex.
“presumably because the assay does not favour third-order interactions.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Figure 2 panels are assigned to the wrong treatment
MinorThe results text attributes an AUF1-silencing result to panels 2g,h, but the caption assigns those panels to AUF1 overexpression and panels 2i,j to silencing.
“Figure 2g,h show that AUF1 overexpression marginally decreased total SNCA mRNA half-life, while AUF1 silencing increased total SNCA mRNA expression by nearly 40% (p < 0.01).”
“The SNCA mRNA stability, 48 h after AUF1 overexpression (g,h) or silencing (i,j), was investigated”
Citations
Cites
Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease
Polymeropoulos, M. H., Lavedan, C., Leroy, E., Ide, S. E., Dehejia, A., Dutra, A., Pike, B., Root, H., Rubenstein, J., Boyer, R., et al. (1997) · Science · doi:10.1126/science.276.5321.2045 · Cited by 8,240
α-Synuclein Locus Triplication Causes Parkinson's Disease
Singleton, A. B., Farrer, M., Johnson, J., Singleton, A., Hague, S., Kachergus, J., Hulihan, M., Peuralinna, T., Dutra, A., Nussbaum, R., et al. (2003) · Science · doi:10.1126/science.1090278 · Cited by 4,383
WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs
Liao, Y., Wang, J., Jaehnig, E. J., Shi, Z., & Zhang, B. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz401 · Cited by 3,144
Spillantini, M. G., Crowther, R. A., Jakes, R., Hasegawa, M., & Goedert, M. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.11.6469 · Cited by 2,868
α-synuclein locus duplication as a cause of familial Parkinson's disease
Chartier-Harlin, M.-C., Kachergus, J., Roumier, C., Mouroux, V., Douay, X., Lincoln, S., Levecque, C., Larvor, L., Andrieux, J., Hulihan, M., et al. (2004) · The Lancet · doi:10.1016/s0140-6736(04)17103-1 · Cited by 2,029
SUnSET, a nonradioactive method to monitor protein synthesis
Schmidt, E. K., Clavarino, G., Ceppi, M., & Pierre, P. (2009) · Nature Methods · doi:10.1038/nmeth.1314 · Cited by 1,706
Kirik, D., Rosenblad, C., Burger, C., Lundberg, C., Johansen, T. E., Muzyczka, N., Mandel, R. J., & Björklund, A. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-07-02780.2002 · Cited by 649
Lo Bianco, C., Ridet, J.-L., Schneider, B. L., Déglon, N., & Aebischer, P. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.152339799 · Cited by 482
An A + U-rich element RNA-binding factor regulates c-myc mRNA stability in vitro.
Brewer, G. (1991) · Molecular and Cellular Biology · doi:10.1128/mcb.11.5.2460 · Cited by 479
Concurrent versus individual binding of HuR and AUF1 to common labile target mRNAs
Lal, A., Mazan‐Mamczarz, K., Kawai, T., Yang, X., Martindale, J. L., & Gorospe, M. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600305 · Cited by 461
Fabian, M. R., Cieplak, M. K., Frank, F., Morita, M., Green, J., Srikumar, T., Nagar, B., Yamamoto, T., Raught, B., Duchaine, T. F., et al. (2011) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2149 · Cited by 329
Dwight, Z., Palais, R. A., & Wittwer, C. T. (2011) · Bioinformatics · doi:10.1093/bioinformatics/btr065 · Cited by 258
Sandler, H., Kreth, J., Timmers, H. T. M., & Stoecklin, G. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr011 · Cited by 221
Pullmann, R., Kim, H. H., Abdelmohsen, K., Lal, A., Martindale, J. L., Yang, X., & Gorospe, M. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.00500-07 · Cited by 199
Metformin‐mediated increase in DICER1 regulates microRNA expression and cellular senescence
Noren Hooten, N., Martin‐Montalvo, A., Dluzen, D. F., Zhang, Y., Bernier, M., Zonderman, A. B., Becker, K. G., Gorospe, M., Cabo, R., & Evans, M. K. (2016) · Aging Cell · doi:10.1111/acel.12469 · Cited by 196
Oliveras-Salvá, M., Van der Perren, A., Casadei, N., Stroobants, S., Nuber, S., D’Hooge, R., Van den Haute, C., & Baekelandt, V. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-44 · Cited by 191
PAR-CLIP analysis uncovers AUF1 impact on target RNA fate and genome integrity
Yoon, J.-H., De, S., Srikantan, S., Abdelmohsen, K., Grammatikakis, I., Kim, J., Kim, K. M., Noh, J. H., White, E. J. F., Martindale, J. L., et al. (2014) · Nature Communications · doi:10.1038/ncomms6248 · Cited by 174
Katila, N., Bhurtel, S., Shadfar, S., Srivastav, S., Neupane, S., Ojha, U., Jeong, G.-S., & Choi, D.-Y. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.08.015 · Cited by 169
Pérez-Revuelta, B. I., Hettich, M. M., Ciociaro, A., Rotermund, C., Kahle, P. J., Krauss, S., & Di Monte, D. A. (2014) · Cell Death & Disease · doi:10.1038/cddis.2014.175 · Cited by 140
Pont, A. R., Sadri, N., Hsiao, S. J., Smith, S., & Schneider, R. J. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.04.019 · Cited by 139
Alternative α-synuclein transcript usage as a convergent mechanism in Parkinson's disease pathology
Rhinn, H., Qiang, L., Yamashita, T., Rhee, D., Zolin, A., Vanti, W., & Abeliovich, A. (2012) · Nature Communications · doi:10.1038/ncomms2032 · Cited by 137
Prion-Like Mechanisms in Parkinson’s Disease
Ma, J., Gao, J., Wang, J., & Xie, A. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00552 · Cited by 134
Jänicke, A., VanCuylenberg, J. B., Boag, P. R., Traven, A., & Beilharz, T. H. (2012) · RNA · doi:10.1261/rna.031898.111 · Cited by 108
AUF1 regulation of coding and noncoding RNA
White, E. J., Matsangos, A. E., & Wilson, G. M. (2016) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1393 · Cited by 107
Locascio, J. J., Eberly, S. W., Liao, Z., Liu, G., Hoesing, A. N., Duong, K. T., Lipsanopoulos, A. T. T., Dhima, K., Hung, A. Y., Flaherty, A. W., et al. (2015) · Brain · doi:10.1093/brain/awv202 · Cited by 94
Saewanee, N., Praputpittaya, T., Malaiwong, N., Chalorak, P., & Meemon, K. (2019) · Neuroscience Research · doi:10.1016/j.neures.2019.12.017 · Cited by 68
Hsiao, K.-Y., Wu, M.-H., Chang, N., Yang, S.-H., Wu, C.-W., Sun, H. S., & Tsai, S.-J. (2015) · Molecular Human Reproduction · doi:10.1093/molehr/gav054 · Cited by 64
Constitutive translation of human α-synuclein is mediated by the 5′-untranslated region
Koukouraki, P., & Doxakis, E. (2016) · Open Biology · doi:10.1098/rsob.160022 · Cited by 58
Self-citationSotiriou, S., Gibney, G., Baxevanis, A. D., & Nussbaum, R. L. (2009) · Neuroscience Letters · doi:10.1016/j.neulet.2009.06.034 · Cited by 57
Structural Remodeling of an A + U-rich RNA Element by Cation or AUF1 Binding
Wilson, G. M., Sutphen, K., Moutafis, M., Sinha, S., & Brewer, G. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m106509200 · Cited by 53
Hussein, A. M., Eldosoky, M., El-Shafey, M., El-Mesery, M., Ali, A. N., Abbas, K. M., & Abulseoud, O. A. (2019) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/cjpp-2018-0266 · Cited by 51
Cardo, L. F., Coto, E., de Mena, L., Ribacoba, R., Lorenzo‐Betancor, O., Pástor, P., Samaranch, L., Mata, I. F., Díaz, M., Morís, G., et al. (2011) · Journal of Molecular Neuroscience · doi:10.1007/s12031-011-9669-1 · Cited by 48
Discovering the 3′ UTR-mediated regulation of alpha-synuclein
Marchese, D., Botta-Orfila, T., Cirillo, D., Rodriguez, J. A., Livi, C. M., Fernández-Santiago, R., Ezquerra, M., Martí, M. J., Bechara, E., Tartaglia, G. G., et al. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx1048 · Cited by 45
miRNA regulons associated with synaptic function
Paschou, M., Paraskevopoulou, M. D., Vlachos, I. S., Koukouraki, P., Hatzigeorgiou, A. G., & Doxakis, E. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046189 · Cited by 41
Self-citationRNA binding proteins: a common denominator of neuronal function and dysfunction
Doxakis, E. (2014) · Neuroscience Bulletin · doi:10.1007/s12264-014-1443-7 · Cited by 40
Self-citationRNA-Binding Proteins Implicated in Mitochondrial Damage and Mitophagy
Ravanidis, S., & Doxakis, E. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00372 · Cited by 36
Self-citationSun, S., Zhang, X., Lyu, L., Li, X., Yao, S., & Zhang, J. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.756908 · Cited by 32
Pan, F.-H., Dong, H., Ding, H., Ye, M., Liu, W., Wu, Y., Zhang, X., Chen, Z.-Y., Luo, Y., & Ding, X. (2012) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2012.01.025 · Cited by 27
Yield of 6,000 proteins by 1D nLC–MS/MS without pre-fractionation
Anagnostopoulos, A. K., Stravopodis, D. J., & Tsangaris, G. T. (2016) · Journal of Chromatography B · doi:10.1016/j.jchromb.2016.08.031 · Cited by 27
Self-citationNeuronal microRNAs modulate TREK two-pore domain K+ channel expression and current density
Paschou, M., Maier, L., Papazafiri, P., Şelescu, T., Dedos, S., Babeș, A., & Doxakis, E. (2020) · RNA Biology · doi:10.1080/15476286.2020.1722450 · Cited by 14
Self-citationCNOT7 Outcompetes Its Paralog CNOT8 for Integration into The CCR4-NOT Complex
Stoney, P. N., Yanagiya, A., Nishijima, S., & Yamamoto, T. S. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167523 · Cited by 13
Fotinos, A., Fritz, D. T., Lisica, S., Liu, Y., & Rogers, M. B. (2016) · Journal of Cellular Biochemistry · doi:10.1002/jcb.25290 · Cited by 8
Kattan, F.-G., Koukouraki, P., Anagnostopoulos, A. K., Tsangaris, G. T., & Doxakis, E. (2023) · Figshare · doi:10.6084/m9.figshare.c.6902598
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Non-coding RNAs in Parkinson's disease: Regulating SNCA and alpha-synuclein aggregation
Thangavelu, L. P., Moglad, E. H. O., Afzal, M., Almalki, W. H., Malathi, H., Bansal, P., Rani, B., Walia, C., Sivaprasad, G. V., Rajput, P., et al. (2024) · Pathology - Research and Practice · doi:10.1016/j.prp.2024.155511 · Cited by 18
Gu, Z., Ding, W., Yuan, S., Peng, Y., Dong, B., Gu, Y., Li, J., Chen, Y., Wang, K., Liu, T., et al. (2024) · Cellular Signalling · doi:10.1016/j.cellsig.2024.111443 · Cited by 6
Wang, X., Xiong, Y., Duan, C., Hu, J., Lu, H., Yang, M., Huang, J., Li, Y. R., Li, Z., Wang, S., et al. (2025) · Journal of Neurology · doi:10.1007/s00415-025-13035-x · Cited by 5
Alpha-synuclein abundance and localization are regulated by the RNA-binding protein PUMILIO1
Cabaj, M., Mazzara, P. G., Gaertner, Z. A., Wang, R., Pauers, M. M., Randolph, L. K., Roque, C. G., Feeney, S., Raimo, S., de Prisco, N., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116145 · Cited by 5
Coupling mechanisms coordinating mRNA translation with stages of the mRNA lifecycle
Famà, V., Tarrero, L. C., Albanese, R., Calviello, L., Biffo, S., Pelizzola, M., & Furlan, M. (2025) · RNA Biology · doi:10.1080/15476286.2025.2483001 · Cited by 3
Zhu, Z., Yu, W., Tang, J., Liang, C., Feng, R., Liu, Y., Zhang, Y., Liu, J., & Gao, Y. (2025) · Journal of Dairy Science · doi:10.3168/jds.2025-26363 · Cited by 2
Doxakis, E., Xue, Y. C., & Savulescu, A. F. (2025) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2025.1716825 · Cited by 2
Self-citationDifferential regulatory role of AU-rich and GU-rich elements in Trypanosoma brucei
Guo, X., Yang, W.-W., Zeng, S., Yue, S., Zhou, L., Zhou, S., Meng, X., & Liu, L. (2026) · Frontiers in Microbiology · doi:10.3389/fmicb.2025.1724550 · Cited by 2
Wang, Y., & Seliger, B. (2024) · OncoImmunology · doi:10.1080/2162402x.2024.2370928 · Cited by 1
Tang, C., Zhu, C., An, Z., Cao, B., Xu, Q., Li, L., Bao, Y., & Li, J. (2026) · Molecular Cancer · doi:10.1186/s12943-026-02599-5 · Cited by 1
Tong, C., Mo, W., Cai, M., Peng, Y., Huang, J., Li, K., & Deng, H. (2026) · Communications Biology · doi:10.1038/s42003-026-09692-x · Cited by 1
hnRNPA1 orchestrates multi-layered regulation of SNCA expressionPreprint
Kattan, F.-G., Anagnostopoulos, A. K., Tsangaris, G. T., & Doxakis, E. (2025) · Research Square · doi:10.21203/rs.3.rs-6294566/v1
Self-citationThe modulation of AUF1 regulates the R-loop resolution activating the immune response in DDR
Ragosta, M. C., di Vaio, A., Maria, C., D’Angelo, M., Medugno, A., Russo, A., Mazzarotti, G., Napolitano, G. M., Iannuzzi, C. A., Forte, I. M., et al. (2026) · iScience · doi:10.1016/j.isci.2026.115900
Xu, C., Peng, Y., Liu, S., Xie, R., Feng, D., Bi, Z., & Yan, L. (2026) · Journal of Virology · doi:10.1128/jvi.00257-26
Han, Q., Huang, S., Luo, S., & Yang, D. (2026) · Biogerontology · doi:10.1007/s10522-026-10464-7
Cheng, Z., Jiang, L., Wang, M., Tang, Q., Zhao, J., Yang, Z., Gu, J., Song, X., Dong, P., Pan, L., et al. (2026) · Oncogene · doi:10.1038/s41388-026-03898-3
Choi, K.-E., & Kim, J. (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1931183
Rozmaric, T. (2026) · reposiTUm (TU Wien) · doi:10.34726/hss.2026.133461
Metadata
- Authors
- Kattan, F.-G., Koukouraki, P., Anagnostopoulos, A. K., Tsangaris, G. T., & Doxakis, E.
- Affiliations
- University of Ioannina (GR)
- Biomedical Research Foundation of the Academy of Athens (GR)
- Corresponding author
- Doxakis, Epaminondas
- Venue
- Open Biology
- Publisher
- The Royal Society
- Published
- 2023-11
- Volume
- 13
- Issue
- 11
- Pages
- 230158-230158
- ISSN
- 2046-2441 (ISSN-L)
- PMC
- PMC10688287
- OpenAlex
- W4388880667
- Semantic Scholar
- 8ea2319d27e5a319337b0768c664cb8c8779d8d8
- Cited by
- 18
- References
- 42
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 3
- FWCI
- 1.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Open Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Empirikion Foundation
- Greek General Secretariat (12RUS-11-65, 2018ΣE01300001, MIS380201)
- Greek State Scholarships Foundation (MIS-5000432)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Keywords
- alpha-synuclein, SNCA, Parkinson's disease, post-transcriptional regulation, 3' untranslated region, RNA-binding proteins, mRNA stability, nuclear export, pre-mRNA splicing, mRNA translation, nucleocytoplasmic shuttling
- MeSH terms
- Heterogeneous Nuclear Ribonucleoprotein D0, Animals, Protein Binding, RNA, Messenger, RNA-Binding Proteins, 3' Untranslated Regions, Active Transport, Cell Nucleus, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
