The DOI matches its Crossref record; 80 of the 82 references it cites were found in a registry or an index; 4 of the 89 sources its claims cite were checked for support.
Distinct Roles for RAB10 and RAB29 in Pathogenic LRRK2-Mediated Endolysosomal Trafficking Alterations
Open accessPublished version of a preprint
Abstract
Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) cause familial Parkinson’s disease, and sequence variations are associated with the sporadic form of the disease. LRRK2 phosphorylates a subset of RAB proteins implicated in secretory and recycling trafficking pathways, including RAB8A and RAB10. Another RAB protein, RAB29, has been reported to recruit LRRK2 to the Golgi, where it stimulates its kinase activity. Our previous studies revealed that G2019S LRRK2 expression or knockdown of RAB8A deregulate epidermal growth factor receptor (EGFR) trafficking, with a concomitant accumulation of the receptor in a RAB4-positive recycling compartment. Here, we show that the G2019S LRRK2-mediated EGFR deficits are mimicked by knockdown of RAB10 and rescued by expression of active RAB10. By contrast, RAB29 knockdown is without effect, but expression of RAB29 also rescues the pathogenic LRRK2-mediated trafficking deficits independently of Golgi integrity. Our data suggest that G2019S LRRK2 deregulates endolysosomal trafficking by impairing the function of RAB8A and RAB10, while RAB29 positively modulates non-Golgi-related trafficking events impaired by pathogenic LRRK2.
Overview
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Written from the paper’s full text.
TL;DR
In HeLa cells, pathogenic G2019S LRRK2 impairs EGFR endolysosomal trafficking by inactivating RAB10 (and RAB8A), while RAB29 expression rescues these deficits independently of Golgi integrity. The data support a model in which RAB8A/RAB10 loss-of-function reduces active RAB7A and causes EGF accumulation in a RAB4-positive recycling compartment.
Key findings
- G2019S LRRK2 expression reduced fluorescent EGF surface binding at 4 °C and impaired degradation of internalized EGF at 37 °C; active RAB10-Q68L fully rescued both, whereas wild-type or inactive RAB10-T23N did not.
- RAB10 knockdown (25 nM siRNA) mimicked G2019S LRRK2 deficits, significantly decreasing EGF binding and EGFR degradation; siRNA-resistant RAB10 rescued, and active RAB7A-Q67L also rescued. RAB10 knockdown reduced endogenous active GTP-bound RAB7 in GST-RILP pulldowns and caused EGF accumulation in a RAB4-positive compartment.
- RAB8A and RAB10 appeared functionally redundant: active RAB8A rescued RAB10-knockdown deficits, and active RAB10 rescued RAB8A-knockdown deficits.
- RAB29 expression rescued G2019S LRRK2-mediated EGF binding/degradation deficits and RAB4 accumulation; RAB29 knockdown had no effect on EGFR trafficking, and brefeldin A did not prevent rescue. Higher RAB29 expression recruited LRRK2 to the Golgi and failed to rescue.
Methods
- HeLa cells were transfected with flag-tagged G2019S LRRK2 and GFP-tagged RAB variants or siRNA (25 nM); EGFR trafficking was measured by fluorescent EGF binding at 4 °C and uptake/degradation at 37 °C at 10 and 30 min, with 20–80 cells analyzed per condition. Colocalization with GFP-RAB4 was quantified in 15–20 cells using Mander’s coefficient.
- Confocal microscopy, Western blotting, and GST-RILP pulldown assays for active RAB7 were used; statistical analysis was one-way ANOVA with Tukey’s post hoc test, significance set at p < 0.05.
Limitations
- Stated: RAB29 knockdown was incomplete and/or transient, so the lack of an EGFR trafficking effect may not exclude a role; future work is needed in dopaminergic neurons or other disease-relevant cell types and with RAB29-specific antibodies; the link between RAB29, LRRK2, and Parkinson’s disease etiology remains unresolved.
- Evident from the text: all experiments used HeLa cells with overexpression and siRNA, not patient neurons or in vivo models; EGFR was the only cargo analyzed; the proposed RAB cascade linking RAB8A/RAB10 inactivation to decreased RAB7A activity is speculative and not directly demonstrated.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
4 of 89 cited sources checked · 1 supported · 0 flagged · accuracy not yet measured
- Findingown data
Knockdown of RAB10 was associated with redistribution of EGF into a vesicular recycling compartment colocalizing with RAB4, which was rescued upon active RAB7A expression.
“knockdown of RAB10 was associated with the redistribution of EGF into a vesicular recycling compartment colocalizing with RAB4, which was rescued upon active RAB7A expression (Figure S3).”
Quote in the paperSubstantial claim - Findingown data
Brefeldin A treatment did not interfere with the RAB29-mediated rescue of the deficits in EGF binding and EGFR degradation owing to G2019S LRRK2.
“it did not interfere with the RAB29-mediated rescue of the deficits in EGF binding and EGFR degradation owing to the presence of G2019S LRRK2 (Figure 6C,D).”
Quote in the paperSubstantial claim - Findingown data
The reported recruitment of LRRK2 to the Golgi complex by RAB29 is only observed when RAB29 is overexpressed to a larger extent.
“Finally, our data show that the reported recruitment of LRRK2 to the Golgi complex by RAB29 [23,54,55,56] is only observed when RAB29 is overexpressed to a larger extent.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [23] Beilina, 2014, Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease, Proc. Natl. Acad. Sci. USA source
Checked before — its earlier verdict is held back until a new check runs.
- cites [54] Liu, 2018, LRRK2 phosphorylates membrane-bound Rabs and is activated by GTP-bound Rab7L1 to promote recruitment to the trans-Golgi network, Hum. Mol. Genet. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [55] Fdez, 2018, RAB7L1-Mediated Relocalization of LRRK2 to the Golgi Complex Causes Centrosomal Deficits via RAB8A, Front. Mol. Neurosci. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [56] Purlyte, 2018, Rab29 activation of the Parkinson’s disease-associated LRRK2 kinase, EMBO J. source
Checked before — its earlier verdict is held back until a new check runs.
- Findingown data
Knockdown of RAB29 was without effect on EGF binding and EGFR degradation.
“Knockdown of RAB29 was without effect on EGF binding and EGFR degradation (Figure S7A–D)”
- Also stated in: § Abstract · plain
“By contrast, RAB29 knockdown is without effect”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
A siRNA-resistant version of RAB10, but not wildtype siRNA-sensitive RAB10, rescued the effect of RAB10 knockdown on EGF binding and EGFR trafficking.
“A siRNA-resistant version of RAB10, but not wildtype siRNA-sensitive RAB10, rescued the effect of RAB10 knockdown on EGF binding and EGFR trafficking (Figure 2E–G)”
Quote in the paperSubstantial claim
- Findingown data
Expression of wildtype RAB29 reverts the accumulation of EGF in a RAB4-positive endocytic compartment induced by knockdown of either RAB10 or RAB8A.
“Expression of wildtype RAB29 also reverted the accumulation of EGF in a RAB4-positive endocytic compartment induced upon knockdown of either RAB10 or RAB8A (Figure S4B,C).”
Quote in the paperSubstantial claim - Findingown data
RAB29 expression rescues the pathogenic LRRK2-mediated endolysosomal trafficking deficits.
“While knockdown of RAB29 was without effect on EGFR trafficking, RAB29 expression rescued the pathogenic LRRK2-mediated endolysosomal trafficking deficits.”
Quote in the paperSubstantial claim - Findingreasoning
The rescue of the LRRK2-mediated deficits upon RAB29 expression occurred in a manner largely independent of Golgi integrity.
“The rescue of the LRRK2-mediated deficits upon RAB29 expression occurred in a manner largely independent of Golgi integrity”
Quote in the paperSubstantial claim - Findingown data
The trafficking deficits mediated by expression of a dominant-negative RAB7A mutant are rescued by RAB29 expression.
“Finally, the trafficking deficits mediated by expression of a dominant-negative RAB7A mutant were rescued by RAB29 expression (Figure S8A–C), as previously described for active RAB8A [31].”
Quote in the paperSubstantial claim - Findingown data
The fraction of endogenous active RAB7 was significantly reduced upon RAB10-siRNA.
“the fraction of endogenous active RAB7 was significantly reduced upon RAB10-siRNA (Figure 3D,E).”
Quote in the paperSubstantial claim - Findingown data
When coexpressed with G2019S LRRK2, RAB29 rescued the LRRK2-mediated decrease in EGF binding and impairment in EGFR degradation.
“When coexpressed with G2019S LRRK2, RAB29 rescued the LRRK2-mediated decrease in EGF binding and the impairment in EGFR degradation (Figure 5B,C).”
Quote in the paperSubstantial claim- The authors state this as an assumption: How variants in the PARK16 locus influence Parkinson's disease risk remains unclear.
- Findingown data
When employing another transfection reagent to achieve higher expression levels, GFP-RAB29 expression caused pronounced recruitment of G2019S LRRK2.
“when employing another transfection reagent to achieve higher expression levels, GFP-RAB29 expression caused a pronounced recruitment of G2019S LRRK2 (Figure S5).”
Quote in the paperSubstantial claim - Findingnone given
The trafficking alterations mediated by pathogenic LRRK2 or knockdown of either RAB8A or RAB10 all converge on decreasing the amounts of GTP-bound, active RAB7.
“The trafficking alterations mediated by pathogenic LRRK2 or knockdown of either RAB8A or RAB10 all converge on decreasing the amounts of GTP-bound, active RAB7.”
Quote in the paperSubstantial claim - Findingown data
Wildtype, but not mutant RAB29 versions rescued the G2019S LRRK2-mediated accumulation of EGF in an RAB4-positive endocytic compartment.
“wildtype, but not mutant RAB29 versions were also found to rescue the G2019S LRRK2-mediated accumulation of EGF in an RAB4-positive endocytic compartment (Figure S4A).”
Quote in the paperSubstantial claim - Findingown data
Expression of the various RAB29 constructs on their own was without effect on EGF binding and EGFR degradation.
“expression of the various RAB29 constructs on their own was without effect (Figure 5D,E)”
Quote in the paperSubstantial claim - Findingown data
Two mutant RAB29 versions previously described to cause RAB29 inactivation did not rescue the LRRK2-mediated endolysosomal trafficking deficits.
“In contrast, two mutant RAB29 versions previously described to cause RAB29 inactivation [23,54,55] did not rescue the LRRK2-mediated endolysosomal trafficking deficits (Figure 5B,C).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [23] Beilina, 2014, Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease, Proc. Natl. Acad. Sci. USA source
Checked before — its earlier verdict is held back until a new check runs.
- cites [54] Liu, 2018, LRRK2 phosphorylates membrane-bound Rabs and is activated by GTP-bound Rab7L1 to promote recruitment to the trans-Golgi network, Hum. Mol. Genet. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [55] Fdez, 2018, RAB7L1-Mediated Relocalization of LRRK2 to the Golgi Complex Causes Centrosomal Deficits via RAB8A, Front. Mol. Neurosci. source
Checked before — its earlier verdict is held back until a new check runs.
- Findingown data
Under higher expression conditions, co-expression of wildtype RAB29 with G2019S LRRK2 failed to rescue the LRRK2-mediated deficits in EGF binding and EGFR degradation, in contrast to low-level RAB29 expression.
“co-expression of wildtype RAB29 with G2019S LRRK2 failed to rescue the LRRK2-mediated deficits in EGF binding and EGFR degradation (Figure S6C,D), in contrast to what was observed with low-level RAB29 expression in parallel experiments (Figure S6E,F).”
Quote in the paperSubstantial claim - Findingown data
Deficits in EGF surface binding and EGFR degradation induced upon siRNA of RAB10 were rescued by overexpressing active GTP-locked RAB7A-Q67L, but not wildtype or GDP-locked RAB7A-T22N.
“the deficits in EGF surface binding and EGFR degradation induced upon siRNA of RAB10 were rescued when overexpressing active, GTP-locked RAB7A (RAB7A-Q67L), but not wildtype or GDP-locked RAB7A (RAB7A-T22N) (Figure 3A,B)”
Quote in the paperSubstantial claim - Findingown data
The decrease in EGF binding and EGFR degradation mediated by knockdown of RAB10 was rescued upon expression of active, but not wildtype or inactive RAB8A.
“the decrease in EGF binding and EGFR degradation mediated by knockdown of RAB10 was rescued upon expression of active, but not wildtype or inactive RAB8A (Figure 4A,B).”
Quote in the paperSubstantial claim - Findingown data
The deficits in EGF binding and EGFR degradation upon siRNA of RAB8A were rescued upon expression of active, but not wildtype or inactive RAB10.
“the deficits in EGF binding and EGFR degradation upon siRNA of RAB8A were rescued upon expression of active, but not wildtype or inactive RAB10 (Figure 4C,D).”
Quote in the paperSubstantial claim - Findingown data
Transient disruption of the Golgi complex by brefeldin A treatment did not alter EGF binding or EGFR trafficking per se.
“transient disruption of the Golgi complex by brefeldin A (BFA) treatment did not alter EGF binding or EGFR trafficking per se (Figure S7E–G)”
Quote in the paperSubstantial claim - Findingown data
Expression of GFP-tagged RAB10 variants on their own was without effect on EGF binding or degradation.
“Expression of GFP-tagged RAB10 variants on their own was without effect on EGF binding or degradation (Figure 1E,F).”
Quote in the paperSubstantial claim - Findingown data
Knockdown of RAB10 was accompanied by a significant decrease in EGF surface binding and EGFR degradation.
“The knockdown of RAB10 was accompanied by a significant decrease in EGF surface binding and EGFR degradation (Figure 2C,D).”
Quote in the paperSubstantial claim - Findingown data
Expression of wildtype, but not inactive, RAB29 variants rescues the deficits in EGF binding and EGFR degradation induced by knockdown of either RAB10 or RAB8A.
“Indeed, expression of wildtype, but not inactive RAB29 variants rescued the deficits in EGF binding and EGFR degradation induced upon knockdown of either RAB10 (Figure 7A–C) or RAB8A (Figure 7D–F)”
Quote in the paperSubstantial claim - Findingown data
Knockdown of RAB29 does not cause endolysosomal trafficking deficits of the EGFR.
“In contrast to RAB8 and RAB10, knockdown of RAB29 did not cause endolysosomal trafficking deficits of the EGFR”
Quote in the paperSubstantial claim - Study design and conductown data
The RAB29 variants used in the rescue experiments were expressed to similar degrees.
“with the RAB29 variants expressed to similar degrees (Figure 7C,F).”
Quote in the paperSubstantial claim - Interpretationown data
RAB29 can rescue the endolysosomal trafficking deficits induced by either G2019S LRRK2 expression or by knockdown of RAB8A or RAB10 in a manner independent of its localization/function at the Golgi complex.
“These data indicate that RAB29 can rescue the endolysosomal trafficking deficits induced by either G2019S LRRK2 expression or by knockdown of RAB8A or RAB10 in a manner independent of its localization/function at the Golgi complex.”
Quote in the paperSubstantial claim - Interpretationown data
RAB8A and RAB10 play functionally redundant roles, at least for the endocytic trafficking/degradation of the EGFR as analyzed here.
“Furthermore, our data indicate that RAB8A and RAB10 play functionally redundant roles, at least for the endocytic trafficking/degradation of the EGFR, as analyzed here.”
Quote in the paperSubstantial claim - Interpretationown data
RAB29 may play role(s) in membrane trafficking in addition to those described at the Golgi complex.
“suggesting that RAB29 may play role(s) in membrane trafficking in addition to those described at the Golgi complex.”
Quote in the paperSubstantial claim - Premisecitation
Previous studies report a beneficial effect of increasing RAB29 protein levels on Golgi-lysosome sorting events, neurite outgrowth, and dopaminergic cell survival in Drosophila neurons.
“This finding is consistent with previous studies reporting a beneficial effect of increasing RAB29 protein levels on Golgi-lysosome sorting events, neurite outgrowth, and dopaminergic cell survival in Drosophila neurons, and with transcriptome analysis suggesting that RAB29 risk variants correlate with a decrease in RAB29 expression levels [22].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] MacLeod, 2013, RAB7L1 Interacts with LRRK2 to Modify Intraneuronal Protein Sorting and Parkinson’s Disease Risk, Neuron source
- Interpretationcitation
Impairing the proper functioning of the RAB8/RAB10-positive perinuclear endocytic recycling compartment is associated with deficits in the complex crosstalk between recycling and degradative vesicular trafficking pathways, with various and potentially disease-relevant cellular outcomes.
“Thus, impairing the proper functioning of the RAB8/RAB10-positive perinuclear endocytic recycling compartment is associated with deficits in the complex crosstalk between recycling and degradative vesicular trafficking pathways, with various and potentially disease-relevant cellular outcomes.”
Quote in the paperSubstantial claim - Interpretationown data
Pathogenic LRRK2 may cause inactivation of RAB10.
“suggesting that pathogenic LRRK2 may cause the inactivation of RAB10.”
Quote in the paperSubstantial claim - Premisecitation
RAB8A and RAB10 colocalize to a perinuclear tubular endocytic recycling compartment.
“This is consistent with their colocalization to a perinuclear tubular endocytic recycling compartment [37,38,39,40]”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [37] Babbey, 2006, Rab10 Regulates Membrane Transport through Early Endosomes of Polarized Madin-Darby Canine Kidney Cells, Mol. Biol. Cell source
- cites [38] Roland, 2009, Alternative Splicing in Class V Myosins Determines Association with Rab10, J. Biol. Chem. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [39] Fdez, 2019, RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase–mediated centrosomal cohesion and ciliogenesis deficits, Hum. Mol. Genet. source
- cites [40] Etoh, 2019, Rab10 regulates tubular endosome formation through KIF13A and KIF13B motors, J. Cell Sci. source
- Premisecitation
LRRK2 plays a role in the endolysosomal system.
“Multiple lines of evidence indicate that LRRK2 plays a role in the endolysosomal system [20]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Fasiczka, 2020, LRRK2-Related Parkinson’s Disease Due to Altered Endolysosomal Biology With Variable Lewy Body Pathology: A Hypothesis, Front. Neurosci. source
Checked before — its earlier verdict is held back until a new check runs.
- Interpretationown data
The LRRK2-mediated deficits in endolysosomal trafficking are the result of a loss-of-function phenotype of either RAB10 or RAB8A, likely triggered by the phosphorylation and concomitant inactivation of these RAB proteins.
“These data are consistent with a model whereby the LRRK2-mediated deficits in endolysosomal trafficking are the result of a loss-of-function phenotype of either RAB10 or RAB8A, likely triggered by the phosphorylation and concomitant inactivation of these RAB proteins.”
Quote in the paperSubstantial claim - Interpretationown data
The effects of RAB10 knockdown on EGF binding and EGFR trafficking were owing to specific knockdown of RAB10.
“indicating that the effects were owing to the specific knockdown of RAB10.”
Quote in the paperSubstantial claim - Interpretationown data
siRNA of RAB10 mimics the endolysosomal trafficking deficits mediated by G2019S LRRK2 expression.
“Thus, siRNA of RAB10 mimics the endolysosomal trafficking deficits mediated by G2019S LRRK2 expression.”
Quote in the paperSubstantial claim- The authors state this as an assumption: The link between RAB10 and the endolysosomal trafficking deficits owing to pathogenic LRRK2 remains unknown.
- Interpretationown data
Under normal conditions, RAB29 is not required for endolysosomal trafficking/degradation of the EGFR.
“suggesting that, under normal conditions, RAB29 is not required for this process.”
Quote in the paperSubstantial claim - Interpretationown data
The RAB29-mediated rescue of the trafficking deficits owing to G2019S LRRK2 expression does not require an intact Golgi complex.
“Thus, the RAB29-mediated rescue of the trafficking deficits owing to G2019S LRRK2 expression does not require an intact Golgi complex.”
Quote in the paperSubstantial claim - Interpretationreasoning
The decrease in RAB7A activity mediated by pathogenic LRRK2 expression occurs by indirect means.
“indicating that the decrease in RAB7A activity mediated by pathogenic LRRK2 expression occurs by indirect means.”
Quote in the paperSubstantial claim - Premisecitation
LRRK2 phosphorylates RAB proteins on their switch II regions, interfering with their binding to most regulatory and effector proteins.
“LRRK2 phosphorylates the RAB proteins on their switch II regions, which consequently interferes with their binding to most regulatory and effector proteins [12,18,19].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [12] Steger, 2017, Systematic proteomic analysis of LRRK2-mediated rab GTPase phosphorylation establishes a connection to ciliogenesis, Elife source
- cites [18] Steger, 2016, Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases, Elife source
- cites [19] Fdez, 2018, Parkinson disease-associated mutations in LRRK2 cause centrosomal defects via Rab8a phosphorylation, Mol. Neurodegener.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning
LRRK2-mediated phosphorylation may cause deficits in the specific membrane trafficking pathways modulated by each RAB protein.
“Therefore, the LRRK2-mediated phosphorylation may cause deficits in the specific membrane trafficking pathways modulated by each of these RAB proteins.”
Quote in the paperSubstantial claim - Interpretationown data
RAB8A and RAB10 perform functionally redundant roles, at least with respect to trafficking of the specific receptor analyzed here.
“RAB8A and RAB10 seem to perform functionally redundant roles, at least with respect to the trafficking of the specific receptor analyzed here.”
Quote in the paperNot a substantial claim - Premisecitation
RAB7A does not serve as a substrate for the LRRK2 kinase activity in vitro or in intact cells.
“RAB7A does not serve as a substrate for the LRRK2 kinase activity in vitro or in intact cells [12,18,31]”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [12] Steger, 2017, Systematic proteomic analysis of LRRK2-mediated rab GTPase phosphorylation establishes a connection to ciliogenesis, Elife source
- cites [18] Steger, 2016, Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases, Elife source
- cites [31] Thomas, 2019, The G2019S variant of leucine-rich repeat kinase 2 (LRRK2) alters endolysosomal trafficking by impairing the function of the GTPase RAB8A, J. Biol. Chem. source
Checked before — its earlier verdict is held back until a new check runs.
- Interpretationcitation
The accumulation of EGF in a RAB4-positive recycling compartment upon pathogenic LRRK2 expression or RNAi of either RAB8A or RAB10 reflects a crosstalk between recycling and degradative trafficking pathways.
“The accumulation of EGF in a RAB4-positive recycling compartment upon pathogenic LRRK2 expression or RNAi of either RAB8A or RAB10 reflects a crosstalk between recycling and degradative trafficking pathways, which has been described before [64,65,66].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [64] McCaffrey, 2001, Rab4 affects both recycling and degradative endosomal trafficking, FEBS Lett. source
- cites [65] Braun, 2015, The Rho-specific GAP protein DLC3 coordinates endocytic membrane trafficking, J. Cell Sci. source
- cites [66] Goueli, 2012, TBC1D16 is a Rab4A GTPase activating protein that regulates receptor recycling and EGF receptor signaling, Proc. Natl. Acad. Sci. USA source
- Interpretationreasoning
The sum of phospho-RAB8 and phospho-RAB10 may be driving the pathogenic LRRK2-mediated vesicular trafficking deficits.
“Thus, the sum of phospho-RAB8 and phospho-RAB10 may be driving the pathogenic LRRK2-mediated vesicular trafficking deficits”
Quote in the paperSubstantial claim
- Probably not a substantial claim. 14
- It may state two separate claims as one. 28
Probably not a substantial claim.
PremisecitationRecent phosphoproteomic analyses identified RAB3, RAB8, RAB10, RAB12, RAB35, and RAB43 as endogenous substrates for LRRK2 activity.
“Recent phosphoproteomic analyses identified a small subset of RAB GTPases (RAB3, RAB8, RAB10, RAB12, RAB35, and RAB43) as endogenous substrates for the LRRK2 activity [12].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [12] Steger, 2017, Systematic proteomic analysis of LRRK2-mediated rab GTPase phosphorylation establishes a connection to ciliogenesis, Elife source
It may state two separate claims as one.
PremisecitationMost endogenous LRRK2 is not present on the Golgi complex, and phospho-RAB8A/RAB10 is not trapped on the Golgi complex under normal conditions.
“This is consistent with findings indicating that most endogenous LRRK2 is not present on the Golgi complex, and that phospho-RAB8A/RAB10 is not trapped on the Golgi complex under normal conditions either [39,55,57].”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [39] Fdez, 2019, RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase–mediated centrosomal cohesion and ciliogenesis deficits, Hum. Mol. Genet. source
The Results section reports that phospho-RAB8/10 accumulates around centrosomes in cells expressing pathogenic LRRK2, but does not assess whether it is trapped on the Golgi under normal conditions. Searches for Golgi localization and endogenous LRRK2 did not find a passage establishing where most endogenous LRRK2 resides; the Golgi mentions found were an antibody in Methods and a reference title. Page numbers were unavailable in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites [55] Fdez, 2018, RAB7L1-Mediated Relocalization of LRRK2 to the Golgi Complex Causes Centrosomal Deficits via RAB8A, Front. Mol. Neurosci. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [57] Gomez, 2019, Membrane association but not identity is required for LRRK2 activation and phosphorylation of Rab GTPases, J. Cell Biol. source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationRAB8 and RAB10 can cooperatively regulate other vesicular trafficking pathways including basolateral sorting, neurite outgrowth, and ciliogenesis.
“and with previous reports showing that RAB8 and RAB10 can cooperatively regulate other vesicular trafficking pathways including basolateral sorting, neurite outgrowth, and ciliogenesis [42,43,44,45].”
Quote in the paperNot a substantial claim2 of 4 sources checked- cites [42] Sato, 2014, Rab8a and Rab8b are essential for several apical transport pathways but insufficient for ciliogenesis, J. Cell Sci.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [43] Schuck, 2007, Rab10 is Involved in Basolateral Transport in Polarized Madin–Darby Canine Kidney Cells, Traffic source
- cites [44] Homma, 2016, Rabin8 regulates neurite outgrowth in both GEF activity-dependent and -independent manners, Mol. Biol. Cell source
The Results section (‘Both Rab8 and Rab10 are involved in neurite outgrowth of PC12 cells’; page unavailable) reports that inhibiting either impairs neurite outgrowth, while suggesting they act independently on different recycling endosomes. The Discussion (‘A Rab cascade on REs and its role during neurite outgrowth’; page unavailable) proposes that Rabin8 activates both; it only speculates about a Rab10 cascade in ciliogenesis and does not establish cooperative Rab8–Rab10 regulation of basolateral sorting. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [45] Tao, 2019, Golgi-resident TRIO regulates membrane trafficking during neurite outgrowth, J. Biol. Chem. source
In “RAB8/RAB10 activation is required for TRIO-mediated neurite outgrowth” (page unavailable), the paper reports that reducing either RAB8 or RAB10 inhibits neurite outgrowth in cerebellar granule neurons. This supports their shared involvement in neurite outgrowth, but our copy does not establish that they cooperatively regulate basolateral sorting or ciliogenesis. (LLM, conf=0.86)
Experimental — accuracy not yet measured
It may state two separate claims as one.
Findingown dataThe endolysosomal deficits mediated by pathogenic LRRK2 are mimicked by knockdown of RAB10 and rescued by expression of active RAB10.
“In the present study, we find that the endolysosomal deficits mediated by pathogenic LRRK2 are mimicked by knockdown of RAB10 and rescued by expression of active RAB10.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThe endolysosomal trafficking deficits mediated by knockdown of RAB10 are rescued by expression of active RAB8A, and the deficits mediated by knockdown of RAB8A are rescued by expression of active RAB10.
“In addition, the endolysosomal trafficking deficits mediated by knockdown of RAB10 are rescued by expression of active RAB8A and vice versa.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
FindingcitationThe deficits in endolysosomal trafficking/degradation of the EGFR caused by RAB10 inactivation are accompanied by accumulation of the receptor in a RAB4-positive recycling compartment and by a decrease in the levels of active, GTP-bound RAB7A.
“The deficits in endolysosomal trafficking/degradation of the EGFR by RAB10 inactivation are accompanied by the accumulation of the receptor in a RAB4-positive recycling compartment, and by a decrease in the levels of active, GTP-bound RAB7A, identical to what we previously described for pathogenic LRRK2 expression or knockdown of RAB8A [30,31].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [30] Fdez, 2014, LRRK2 delays degradative receptor trafficking by impeding late endosomal budding through decreasing Rab7 activity, Hum. Mol. Genet. source
- cites [31] Thomas, 2019, The G2019S variant of leucine-rich repeat kinase 2 (LRRK2) alters endolysosomal trafficking by impairing the function of the GTPase RAB8A, J. Biol. Chem. source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
Findingown dataGFP-tagged RAB29 largely colocalized with a Golgi marker, and coexpression with G2019S LRRK2 did not result in efficient recruitment of LRRK2 to the Golgi complex.
“while GFP-tagged RAB29 largely colocalized with a Golgi marker, coexpression of RAB29 with flag-tagged G2019S LRRK2 revealed that this did not result in the efficient recruitment of LRRK2 to the Golgi complex (Figure 5A).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataWhen co-expressed with pathogenic G2019S LRRK2, active RAB10-Q68L fully rescued the decrease in EGF binding and the impairment in EGFR degradation, which was not observed with wildtype RAB10 or inactive RAB10 variant.
“when co-expressed with pathogenic G2019S LRRK2, active RAB10-Q68L fully rescued the decrease in EGF binding and the impairment in EGFR degradation, which was not observed with wildtype RAB10 or with the inactive RAB10 variant (Figure 1C,D)”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataG2019S LRRK2 expression reduces EGF binding at 4°C and impairs clearance/degradation of internalized fluorescent EGF at 37°C.
“expression of flag-tagged G2019S LRRK2 reduced the binding of fluorescent EGF at 4 °C, and impaired the clearance/degradation of internalized fluorescent EGF upon incubation of cells at 37 °C (Figure 1A–D).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe G2019S mutation in LRRK2 increases its kinase activity in vitro and in vivo.
“the most prominent pathogenic mutation (G2019S) situated within the kinase domain increases its activity in vitro as well as in vivo”
Quote in the paperNot a substantial claim0 of 8 sources checked- cites [4] Greggio, 2006, Kinase activity is required for the toxic effects of mutant LRRK2/dardarin, Neurobiol. Dis. source
- cites [5] Smith, 2006, Kinase activity of mutant LRRK2 mediates neuronal toxicity, Nat. Neurosci. source
- cites [6] Jaleel, 2007, LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson’s disease mutants affect kinase activity, Biochem. J. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [7] West, 2007, Parkinson’s disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity, Hum. Mol. Genet. source
- cites [8] Delgado, 2007, Mechanistic insight into the dominant mode of the Parkinson’s disease-associated G2019S LRRK2 mutation, Hum. Mol. Genet. source
- cites [9] Lee, 2010, Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson’s disease, Nat. Med. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [10] Stafa, K., Trancikova, A., Webber, P.J., Glauser, L., West, A.B., and Moore, D.J. (2012). GTPase activity and neuronal toxicity of parkinson’s disease-associated LRRK2 is regulated by ArfGAP1. PLoS Genet., 8. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [11] Hatcher, 2017, Small-Molecule Inhibitors of LRRK2, Adv Neurobiol. source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationMutations in the LRRK2 gene are a common cause of familial Parkinson's disease and are also observed in sporadic Parkinson's disease patients.
“Mutations in the LRRK2 gene are a common cause of familial Parkinson’s disease (PD) and are also observed in sporadic PD patients, indicating a key role for LRRK2 across the entire disease spectrum [1,2,3].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [1] Alessi, 2018, LRRK2 kinase in Parkinson’s disease, Science source
Checked before — its earlier verdict is held back until a new check runs.
- cites [2] Schulte, 2009, Genome-wide association study reveals genetic risk underlying Parkinson’s disease, Nat. Genet. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [3] Kluss, 2019, LRRK2 links genetic and sporadic Parkinson’s disease, Biochem. Soc. Trans. source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationPrevious studies indicate that RAB29 colocalizes and interacts with RAB8, and regulates receptor recycling in T cells as well as the trafficking of endosome-derived ciliary cargo at the base of the cilium.
“Indeed, previous studies indicate that RAB29 colocalizes and interacts with RAB8, and regulates receptor recycling in T cells as well as the trafficking of endosome-derived ciliary cargo at the base of the cilium [75].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [75] Onnis, 2015, The small GTPase Rab29 is a common regulator of immune synapse assembly and ciliogenesis, Cell Death Differ. source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
Interpretationown dataG2019S LRRK2 deregulates endolysosomal trafficking by impairing function of RAB8A and RAB10, while RAB29 positively modulates non-Golgi-related trafficking events impaired by pathogenic LRRK2.
“Our data suggest that G2019S LRRK2 deregulates endolysosomal trafficking by impairing the function of RAB8A and RAB10, while RAB29 positively modulates non-Golgi-related trafficking events impaired by pathogenic LRRK2.”
Quote in the paperSubstantial claim- The authors state this as an assumption: The precise mechanisms linking LRRK2 to the endolysosomal system remain poorly defined.
- The authors state this as an assumption: The link between RAB10 and the endolysosomal trafficking deficits owing to pathogenic LRRK2 remains unknown.
- The authors state this as an assumption: How variants in the PARK16 locus influence Parkinson's disease risk remains unclear.
It may state two separate claims as one.
PremisecitationKnockdown or knockout of RAB29 causes deficits in retrograde sorting events between the late endosome and the Golgi complex, which is crucial for the correct trafficking of lysosomal enzymes and associated with defects in lysosomal homeostasis.
“However, knockdown or knockout of RAB29 causes deficits in retrograde sorting events between the late endosome and the Golgi complex, which is crucial for the correct trafficking of lysosomal enzymes and associated with defects in lysosomal homeostasis [22,27,74].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [22] MacLeod, 2013, RAB7L1 Interacts with LRRK2 to Modify Intraneuronal Protein Sorting and Parkinson’s Disease Risk, Neuron source
- cites [27] Beilina, 2020, The Parkinson’s Disease Protein LRRK2 Interacts with the GARP Complex to Promote Retrograde Transport to the trans-Golgi Network, Cell Rep. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [74] Kuwahara, 2016, LRRK2 and RAB7L1 coordinately regulate axonal morphology and lysosome integrity in diverse cellular contexts, Sci. Rep. source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationRAB10 is widely expressed in peripheral tissues and brain, present in all cell types, and localized to a tubular perinuclear endocytic recycling compartment partially overlapping with RAB8A.
“It is widely expressed in peripheral tissues as well as in the brain, where it is present in all cell types [36], and localized to a tubular perinuclear endocytic recycling compartment partially overlapping with RAB8A [37,38,39,40].”
Quote in the paperNot a substantial claim0 of 5 sources checked- cites [36] Zhang, 2016, Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse, Neuron source
- cites [37] Babbey, 2006, Rab10 Regulates Membrane Transport through Early Endosomes of Polarized Madin-Darby Canine Kidney Cells, Mol. Biol. Cell source
- cites [38] Roland, 2009, Alternative Splicing in Class V Myosins Determines Association with Rab10, J. Biol. Chem. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [39] Fdez, 2019, RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase–mediated centrosomal cohesion and ciliogenesis deficits, Hum. Mol. Genet. source
- cites [40] Etoh, 2019, Rab10 regulates tubular endosome formation through KIF13A and KIF13B motors, J. Cell Sci. source
It may state two separate claims as one.
Interpretationown dataImpairing function of either RAB8A or RAB10 causes endolysosomal trafficking deficits identical to G2019S LRRK2 expression, associated with decrease in RAB7 activity and culminating in accumulation of EGF in a non-degradative RAB4-positive recycling compartment.
“Thus, impairing the function of either RAB8A or RAB10 causes endolysosomal trafficking deficits identical to G2019S LRRK2 expression, which are associated with a decrease in RAB7 activity and culminate in the accumulation of EGF in a non-degradative, RAB4-positive recycling compartment.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
PremisecitationPathogenic G2019S LRRK2 expression causes deficits in Golgi-lysosome-related sorting events, which are mimicked by knockdown of RAB29 and rescued by RAB29 overexpression, and decreased RAB29 levels correlate with increased Parkinson's disease risk.
“pathogenic G2019S LRRK2 expression causes deficits in Golgi-lysosome-related sorting events, which are mimicked by knockdown of RAB29 and rescued by RAB29 overexpression, respectively, and transcriptome and protein analyses indicate that decreased RAB29 levels correlate with increased PD risk [22].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [22] MacLeod, 2013, RAB7L1 Interacts with LRRK2 to Modify Intraneuronal Protein Sorting and Parkinson’s Disease Risk, Neuron source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationOther studies reported a physical interaction between LRRK2 and RAB29, and when overexpressed, RAB29 can recruit LRRK2 to the Golgi network.
“Other studies have reported a physical interaction between LRRK2 and RAB29, and when overexpressed, RAB29 can recruit LRRK2 to the Golgi network [23,54,55,56].”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [23] Beilina, 2014, Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease, Proc. Natl. Acad. Sci. USA source
Checked before — its earlier verdict is held back until a new check runs.
- cites [54] Liu, 2018, LRRK2 phosphorylates membrane-bound Rabs and is activated by GTP-bound Rab7L1 to promote recruitment to the trans-Golgi network, Hum. Mol. Genet. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [55] Fdez, 2018, RAB7L1-Mediated Relocalization of LRRK2 to the Golgi Complex Causes Centrosomal Deficits via RAB8A, Front. Mol. Neurosci. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [56] Purlyte, 2018, Rab29 activation of the Parkinson’s disease-associated LRRK2 kinase, EMBO J. source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationTranscriptome analysis suggests that RAB29 risk variants correlate with a decrease in RAB29 expression levels.
“and with transcriptome analysis suggesting that RAB29 risk variants correlate with a decrease in RAB29 expression levels [22].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] MacLeod, 2013, RAB7L1 Interacts with LRRK2 to Modify Intraneuronal Protein Sorting and Parkinson’s Disease Risk, Neuron source
It may state two separate claims as one.
PremisecitationPathogenic LRRK2 expression impairs endolysosomal degradative trafficking and endocytic recycling of EGFR, with decreased active GTP-bound RAB7A and accumulation of the receptor in a RAB4-positive recycling compartment.
“Pathogenic LRRK2 expression was found to impair the endolysosomal degradative trafficking as well as the endocytic recycling of the EGFR, with a concomitant decrease in the levels of active, GTP-bound RAB7A, and an accumulation of the receptor in a RAB4-positive recycling compartment [30,31].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [30] Fdez, 2014, LRRK2 delays degradative receptor trafficking by impeding late endosomal budding through decreasing Rab7 activity, Hum. Mol. Genet. source
- cites [31] Thomas, 2019, The G2019S variant of leucine-rich repeat kinase 2 (LRRK2) alters endolysosomal trafficking by impairing the function of the GTPase RAB8A, J. Biol. Chem. source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. It may state two separate claims as one.
PremisecitationRAB29-mediated recruitment stimulates LRRK2 kinase activity and causes accumulation of phospho-RABs in the same membrane compartment, likely because phospho-proteins are unable to be extracted by GDI.
“Such recruitment stimulates the LRRK2 kinase activity and causes an accumulation of phospho-RABs in the same membrane compartment, likely because the phospho-proteins are unable to be extracted by GDI [56,57].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [56] Purlyte, 2018, Rab29 activation of the Parkinson’s disease-associated LRRK2 kinase, EMBO J. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [57] Gomez, 2019, Membrane association but not identity is required for LRRK2 activation and phosphorylation of Rab GTPases, J. Cell Biol. source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
Study design and conductown dataBrefeldin A treatment caused perinuclear dispersal of a Golgi marker as well as of GFP-RAB29.
“while BFA treatment caused the perinuclear dispersal of a Golgi marker as well as of GFP-RAB29 (Figure 6A,B)”
Quote in the paperSubstantial claimIt may state two separate claims as one.
InterpretationcitationDeficits in the trafficking/degradation of the EGFR may not have been evident owing to the incomplete and/or transient nature of the RAB29 knockdown, because alterations in the correct processing of lysosomal hydrolases have only been described in RAB29 knockout contexts, and may thus only arise as a consequence of the prolonged missorting of cargo.
“Deficits in the trafficking/degradation of the EGFR may not have been evident owing to the incomplete and/or transient nature of the RAB29 knockdown, because alterations in the correct processing of lysosomal hydrolases have only been described in RAB29 knockout contexts, and may thus only arise as a consequence of the prolonged missorting of cargo [27,74].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [27] Beilina, 2020, The Parkinson’s Disease Protein LRRK2 Interacts with the GARP Complex to Promote Retrograde Transport to the trans-Golgi Network, Cell Rep. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [74] Kuwahara, 2016, LRRK2 and RAB7L1 coordinately regulate axonal morphology and lysosome integrity in diverse cellular contexts, Sci. Rep. source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim.
PremisecitationRAB10 serves as a prominent LRRK2 kinase substrate in all cell lines and tissues analyzed.
“RAB10 serves as a prominent LRRK2 kinase substrate in all cell lines and tissues analyzed [12,18,32,33,34,35].”
Quote in the paperSubstantial claim0 of 6 sources checked- cites [12] Steger, 2017, Systematic proteomic analysis of LRRK2-mediated rab GTPase phosphorylation establishes a connection to ciliogenesis, Elife source
- cites [18] Steger, 2016, Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases, Elife source
- cites [32] Fdez, 2019, Centrosomal cohesion deficits as cellular biomarker in lymphoblastoid cell lines from LRRK2 Parkinson’s disease patients, Biochem. J. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [33] Lis, 2018, Development of phospho-specific Rab protein antibodies to monitor in vivo activity of the LRRK2 Parkinson’s disease kinase, Biochem. J. source
- cites [34] Fan, 2018, Interrogating Parkinson’s disease LRRK2 kinase pathway activity by assessing Rab10 phosphorylation in human neutrophils, Biochem. J. source
- cites [35] Atashrazm, 2019, LRRK2-mediated Rab10 phosphorylation in immune cells from Parkinson’s disease patients, Mov. Disord. source
It may state two separate claims as one.
Interpretationown dataThe RAB29-mediated recruitment of LRRK2 to the Golgi complex is only evident upon higher expression levels, and is associated with impairment of the RAB29-mediated rescue of endolysosomal trafficking deficits owing to G2019S LRRK2 expression.
“the RAB29-mediated recruitment of LRRK2 to the Golgi complex is only evident upon higher expression levels, and is associated with an impairment of the RAB29-mediated rescue of the endolysosomal trafficking deficits owing to G2019S LRRK2 expression.”
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.
PremisecitationRAB10 modulates a variety of membrane trafficking events including exocytic polarized targeting and endocytic recycling, and can perform functions partially redundant with RAB8A.
“RAB10 has been described to modulate a variety of membrane trafficking events including exocytic polarized targeting and endocytic recycling events [41], and can perform functions partially redundant with those of RAB8A [42,43,44,45].”
Quote in the paperNot a substantial claim0 of 5 sources checked- cites [41] Chua, 2018, Rab 10—A traffic controller in multiple cellular pathways and locations, J. Cell. Physiol. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [42] Sato, 2014, Rab8a and Rab8b are essential for several apical transport pathways but insufficient for ciliogenesis, J. Cell Sci.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [43] Schuck, 2007, Rab10 is Involved in Basolateral Transport in Polarized Madin–Darby Canine Kidney Cells, Traffic source
- cites [44] Homma, 2016, Rabin8 regulates neurite outgrowth in both GEF activity-dependent and -independent manners, Mol. Biol. Cell source
Checked before — its earlier verdict is held back until a new check runs.
- cites [45] Tao, 2019, Golgi-resident TRIO regulates membrane trafficking during neurite outgrowth, J. Biol. Chem. source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
Study design and conductown dataKnockdown of RAB10 caused a pronounced decrease in RAB10 protein levels 48 h post-transfection, while steady-state levels of RAB8A and RAB7A remained unchanged.
“Knockdown of RAB10 caused a pronounced decrease in RAB10 protein levels 48 h post-transfection (Figure 2A,B), while the steady-state levels of several other RAB proteins including RAB8A (Figure 2A,B) or RAB7A remained unchanged (Figure S2).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
PremisecitationAll alterations due to pathogenic LRRK2 expression were mimicked by knockdown of RAB8A and rescued by expression of active RAB8A, suggesting they are mediated at least in part by RAB8A inactivation.
“All alterations due to pathogenic LRRK2 expression were mimicked by knockdown of RAB8A and rescued by expression of active RAB8A, suggesting that they are mediated, at least in part, by RAB8A inactivation [31].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] Thomas, 2019, The G2019S variant of leucine-rich repeat kinase 2 (LRRK2) alters endolysosomal trafficking by impairing the function of the GTPase RAB8A, J. Biol. Chem. source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationInterfering with the integrity/function of the RAB8-positive early recycling compartment causes impaired degradation of the EGFR, which consequently accumulates in a RAB4-positive recycling compartment.
“and interfering with the integrity/function of the RAB8-positive early recycling compartment causes impaired degradation of the EGFR, which consequently accumulates in a RAB4-positive recycling compartment [65].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [65] Braun, 2015, The Rho-specific GAP protein DLC3 coordinates endocytic membrane trafficking, J. Cell Sci. source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationRAB29 is contained within the PARK16 locus, which is linked to Parkinson's disease.
“RAB29 is contained within the PARK16 locus, which is linked to Parkinson’s disease”
Quote in the paperNot a substantial claim0 of 8 sources checked- cites [2] Schulte, 2009, Genome-wide association study reveals genetic risk underlying Parkinson’s disease, Nat. Genet. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [46] Tucci, 2010, Genetic variability at the PARK16 locus, Eur. J. Hum. Genet. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [47] Dahary, 2012, Association of Sequence Alterations in the Putative Promoter of RAB7L1 With a Reduced Parkinson Disease Risk, Arch. Neurol. source
- cites [48] Guo, 2014, An association analysis of the rs1572931 polymorphism of the RAB7L1 gene in Parkinson’s disease, amyotrophic lateral sclerosis and multiple system atrophy in China, Eur. J. Neurol. source
- cites [49] Rengmark, 2015, Fine mapping and resequencing of the PARK16 locus in Parkinson’s disease, J. Hum. Genet. source
- cites [50] Khaligh, 2017, RAB7L1 promoter polymorphism and risk of Parkinson’s disease; a case-control study, Neurol. Res. source
- cites [51] He, 2017, Association between PARK16 and Parkinson’s disease: A meta-analysis, Neurosci. Lett. source
- cites [52] Goudarzian, 2015, The rs1572931 polymorphism of the RAB7L1 gene promoter is associated with reduced risk of Parkinson’s disease, Neurol. Res. source
It may state two separate claims as one.
PremisecitationVariants within the RAB29 and LRRK2 loci seem to impact Parkinson's disease in a non-additive manner, suggesting the two proteins function in a common cellular pathway.
“Variants within the RAB29 and the LRRK2 locus seem to impact PD in a non-additive manner [22,49,53], suggesting that the two proteins function in a common cellular pathway.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [22] MacLeod, 2013, RAB7L1 Interacts with LRRK2 to Modify Intraneuronal Protein Sorting and Parkinson’s Disease Risk, Neuron source
- cites [49] Rengmark, 2015, Fine mapping and resequencing of the PARK16 locus in Parkinson’s disease, J. Hum. Genet. source
- cites [53] Heckman, 2013, GWAS risk factors in Parkinson’s disease: LRRK2 coding variation and genetic interaction with PARK16, Am. J. Neurodegener. Dis.
It may state two separate claims as one.
Interpretationown dataThe LRRK2-mediated endolysosomal trafficking deficits are neither mimicked by RAB29 inactivation nor dependent on Golgi integrity.
“suggesting that the LRRK2-mediated endolysosomal trafficking deficits are neither mimicked by RAB29 inactivation nor dependent on Golgi integrity.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationExpression of a dominant-negative RAB4 construct alters both endocytic recycling and degradation events.
“For example, expression of a dominant-negative RAB4 construct alters both endocytic recyling and degradation events [64]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [64] McCaffrey, 2001, Rab4 affects both recycling and degradative endosomal trafficking, FEBS Lett. source
It may state two separate claims as one.
Interpretationown dataPathogenic LRRK2 expression causes endolysosomal trafficking alterations by impairing RAB10 function, and these alterations are rescued by RAB29 independent of its Golgi localization.
“Pathogenic LRRK2 expression causes endolysosomal trafficking alterations by impairing RAB10 function, and these alterations are rescued by RAB29 independent of its Golgi localization.”
Quote in the paperSubstantial claim- The authors state this as an assumption: The precise mechanisms linking LRRK2 to the endolysosomal system remain poorly defined.
- The authors state this as an assumption: The link between RAB10 and the endolysosomal trafficking deficits owing to pathogenic LRRK2 remains unknown.
- The authors state this as an assumption: How variants in the PARK16 locus influence Parkinson's disease risk remains unclear.
The authors state this as an assumption.
The precise mechanisms linking LRRK2 to the endolysosomal system remain poorly defined.
“However, the precise underlying mechanisms remain poorly defined.”
The authors state this as an assumption.
The link between RAB10 and the endolysosomal trafficking deficits owing to pathogenic LRRK2 remains unknown.
“However, the link between RAB10 and the endolysosomal trafficking deficits owing to pathogenic LRRK2 remains unknown.”
The authors state this as an assumption.
How variants in the PARK16 locus influence Parkinson's disease risk remains unclear.
“even though it remains unclear how variants in this locus influence disease risk”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Self-check results appear here once an independent check has confirmed them.
Cited works that were retracted
Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.
Cites a retracted work: 10.7554/elife.12248
MajorThe cited work was retracted on 2018-04-12 (notice 10.7554/elife.37048), before this paper was published (2020-07-17). Its authors could have known.
Cited work 10.7554/elife.12248 · retracted 2018-04-12 · notice 10.7554/elife.37048 · this paper published 2020-07-17
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Analysis of zebrafish Lrrk2 loss-of-function during brain development and adult brain regeneration
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Metadata
- Authors
- Rivero-Ríos, P., Romo-Lozano, M., Fernández, B., Fdez, E., & Hilfiker, S.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Institute of Parasitology and Biomedicine “López-Neyra”, Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Hilfiker, Sabine
- Venue
- Cells
- Publisher
- MDPI AG
- Published
- 2020-07-17
- Volume
- 9
- Issue
- 7
- Pages
- 1719
- ISSN
- 2073-4409 (ISSN-L)
- PMC
- PMC7407826
- OpenAlex
- W3043088877
- Semantic Scholar
- b9b16791c373808db2422f7d62a7f3da36a519e1
- Cited by
- 38
- References
- 82
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 9 · 2023: 9 · 2022: 5 · 2021: 5 · 2020: 1
- FWCI
- 1.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cells (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Ministerio de Economía, Industria y Competitividad, Gobierno de España (SAF2017-89402-R)
- The Michael J Fox Foundation (N.A.)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- LRRK2, Rab10, Rab29, Rab8a, endolysosomal trafficking, Parkinson's disease, EGFR trafficking, Golgi apparatus, receptor trafficking
- MeSH terms
- Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, rab7 GTP-Binding Proteins, Epidermal Growth Factor, Golgi Apparatus, HeLa Cells, Humans, Lysosomes, Mutation, Endosomes, rab GTP-Binding Proteins, rab4 GTP-Binding Proteins, Protein Transport, Gene Knockdown Techniques, Proteolysis
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 ›
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