Cellular and subcellular localization of Rab10 and phospho-T73 Rab10 in the mouse and human brain

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

G2019S-LRRK2 accounts for 30-41% of familial Parkinson's disease cases and 10% of sporadic Parkinson's disease.

“The G2019S-LRRK2 mutations accounts for 30–41% of all familial cases, and 10% of sporadic PD [23, 31, 38, 39, 57, 58, 68, 99].”

• cites [23] Healy DG, Falchi M, O’Sullivan SS, Bonifati V, Durr A, Bressman S, Brice A, Aasly J, Zabetian CP, Goldwurm S et al (2008) Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol 7:583–590. https://doi.org/10.1016/S1474-4422(08)70117-0 sourceDisputed

  The Results report worldwide frequencies of 4% in hereditary PD and 1% in sporadic PD, contrary to the claim about all familial and sporadic cases. The higher figures apply to particular populations: 36% of hereditary cases among North African Arabs and 10% of sporadic cases among Ashkenazi Jews. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites [31] Kumari U, Tan EK (2009) LRRK2 in Parkinson’s disease: genetic and clinical studies from patients. FEBS J 276:6455–6463. https://doi.org/10.1111/j.1742-4658.2009.07344.x sourcePartly supported

  The “Prevalence of LRRK2 G2019S mutation” section (page not provided) reports familial rates of 29.7% among Ashkenazi Jews and 37.0% among North African Arabs, but not 30–41% of all familial cases. It reports sporadic rates of 13.3% and 40.8% in those groups, not a general rate of 10%; rates in most Caucasian populations are much lower. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [38] Lesage S, Durr A, Tazir M, Lohmann E, Leutenegger AL, Janin S, Pollak P, Brice A, French Parkinson’s Disease Genetics Study G (2006) LRRK2 G2019S as a cause of Parkinson’s disease in North African Arabs. N Engl J Med 354:422–423. https://doi.org/10.1056/NEJMc055540 sourcePartly supported

  Table 1 reports 30% and 41% in separate studies of familial Parkinson’s disease among North African Arabs, supporting that range only for this population. It reports 41%, not 10%, in sporadic cases; the paper does not establish these percentages for all Parkinson’s disease cases. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Rab10 plays a critical role in development, as evidenced by the lethality of a Rab10 double knockout in mice.

“Rab10 also plays a critical role in development as evidenced by the lethality of a Rab10 double knock out in mice [45].”

• cites [45] Lv P, Sheng Y, Zhao Z, Zhao W, Gu L, Xu T, Song E (2015) Targeted disruption of Rab10 causes early embryonic lethality. Protein Cell 6:463–467. https://doi.org/10.1007/s13238-015-0150-8 sourceSupported

Probably not a substantial claim. The paper’s conclusions may not depend on it.

LRRK2 localizes to microglia and astrocytes.

“Glial cells make up roughly half of the cells in the central nervous system (CNS) and LRRK2 has been shown to localize to microglia and astrocytes [30, 55, 80, 97].”

• cites [30] Khan SS, Sobu Y, Dhekne HS, Tonelli F, Berndsen K, Alessi DR, Pfeffer SR (2021) Pathogenic LRRK2 control of primary cilia and Hedgehog signaling in neurons and astrocytes of mouse brain. Elife 10:1. https://doi.org/10.7554/eLife.67900 sourcePartly supported

  The Results section, “Ciliary defects in G2019S striatal astrocytes” (page unavailable), states that mouse LRRK2 is expressed in astrocytes. Our copy does not establish its localization to microglia, so the claim is supported only for astrocytes. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [55] Moehle MS, Webber PJ, Tse T, Sukar N, Standaert DG, DeSilva TM, Cowell RM, West AB (2012) LRRK2 inhibition attenuates microglial inflammatory responses. J Neurosci 32:1602–1611. https://doi.org/10.1523/JNEUROSCI.5601-11.2012 sourcePartly supported

  The Results (‘LRRK2 expression in TLR4-activated microglia’) show LRRK2 in activated microglia and in primary astrocytes grown in culture. The same section says the authors could not observe astrocyte expression in vivo, while resting microglia did not show LRRK2 immunoreactivity. The unqualified claim therefore extends beyond the conditions demonstrated. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [80] Streubel-Gallasch L, Giusti V, Sandre M, Tessari I, Plotegher N, Giusto E, Masato A, Iovino L, Battisti I, Arrigoni G et al (2021) Parkinson’s disease-associated LRRK2 interferes with astrocyte-mediated alpha-synuclein clearance. Mol Neurobiol 58:3119–3140. https://doi.org/10.1007/s12035-021-02327-8 sourceSupported
• cites [97] Zaldivar-Diez J, Li L, Garcia AM, Zhao WN, Medina-Menendez C, Haggarty SJ, Gil C, Morales AV, Martinez A (2020) Benzothiazole-based LRRK2 inhibitors as wnt enhancers and promoters of oligodendrocytic fate. J Med Chem 63:2638–2655. https://doi.org/10.1021/acs.jmedchem.9b01752 sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

LRRK2 is expressed in the cortex, substantia nigra pars compacta, and striatum of the rodent brain, particularly in layer V pyramidal neurons in the cortex and spiny projection neurons in the striatum.

“A previous study by our group showed that LRRK2 is expressed in the cortex, SNc, and in the striatum of the rodent brain particularly in layer V pyramidal neurons in the cortex, and spiny projection neurons in the striatum [73, 90].”

• cites [73] Simon-Sanchez J, Herranz-Perez V, Olucha-Bordonau F, Perez-Tur J (2006) LRRK2 is expressed in areas affected by Parkinson’s disease in the adult mouse brain. Eur J Neurosci 23:659–666. https://doi.org/10.1111/j.1460-9568.2006.04616.x sourceNot checked — no full text of the source
• cites [90] West AB, Cowell RM, Daher JP, Moehle MS, Hinkle KM, Melrose HL, Standaert DG, Volpicelli-Daley LA (2014) Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents. J Comp Neurol 522:2465–2480. https://doi.org/10.1002/cne.23583 sourcePartly supported

  The Results sections on rodent motor cortex and striatum identify LRRK2 in layer V pyramidal neurons and medium spiny neurons, respectively. The Results section on the rodent SNpc reports expression in mice but no detectable LRRK2 in the examined rat dopaminergic neurons, so the unqualified statement about the rodent SNc misses a species distinction. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

Rab10 localizes at ER membranes and plays a role in ER dynamics and maintaining morphology.

“Rab10 has been shown to localize at ER membranes and play a role in ER dynamics and maintaining morphology [17].”

• cites [17] English AR, Voeltz GK (2013) Rab10 GTPase regulates ER dynamics and morphology. Nat Cell Biol 15:169–178. https://doi.org/10.1038/ncb2647 sourceSupported

Probably not a substantial claim.

SATB2 is a marker of excitatory neurons.

“Immunofluorescence for special AT-rich sequence binding protein2 (SATB2), a marker of excitatory neurons [27], was present in all layers except for layer 1 which is mostly composed of dendrites and axons (Fig. 2 a, c).”

• cites [27] Huang Y, Song NN, Lan W, Hu L, Su CJ, Ding YQ, Zhang L (2013) Expression of transcription factor Satb2 in adult mouse brain. Anat Rec (Hoboken) 296:452–461. https://doi.org/10.1002/ar.22656 sourceSupported

Probably not a substantial claim. It may state two separate claims as one.

Most mutations in LRRK2 increase its kinase activity, increasing phosphorylation of a broad subset of Rab GTPases.

“Most mutations in LRRK2 increase its kinase activity, increasing phosphorylation of a broad subset of Rab GTPases [79].”

• cites [79] Steger M, Tonelli F, Ito G, Davies P, Trost M, Vetter M, Wachter S, Lorentzen E, Duddy G, Wilson S et al (2016) Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. Elife 5:1. https://doi.org/10.7554/eLife.12813 sourcePartly supported

  The Introduction says that PD-associated LRRK2 mutations increase phosphorylation of at least three Rab GTPases, supporting increased phosphorylation of a subset, but not characterizing that subset as broad. The Results section on pathogenic mutations distinguishes kinase-domain mutations that augment kinase activity from the ROC-COR mutation R1441C, which increased Rab phosphorylation in cells without directly enhancing kinase activity. The paper therefore does not support the claim that most mutations increase kinase activity as the mechanism. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Rab10 is involved in recycling and present at the trans-Golgi network (TGN).

“In addition, previously it has been shown that Rab10 is involved recycling and present at the trans-Golgi network (TGN) [12, 72].”

• cites [12] Chen CC, Schweinsberg PJ, Vashist S, Mareiniss DP, Lambie EJ, Grant BD (2006) RAB-10 is required for endocytic recycling in the Caenorhabditis elegans intestine. Mol Biol Cell 17:1286–1297. https://doi.org/10.1091/mbc.e05-08-0787 sourcePartly supported

  The Results (page unavailable) support a role for RAB-10 in recycling in the C. elegans intestine. They describe TGN localization more cautiously: RAB-10-labeled structures are “probably TGN,” with significant residence on “TGN and/or apical recycling endosomes.” The claim presents TGN localization as definite. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [72] Schuck S, Gerl MJ, Ang A, Manninen A, Keller P, Mellman I, Simons K (2007) Rab10 is involved in basolateral transport in polarized Madin-Darby canine kidney cells. Traffic 8:47–60. https://doi.org/10.1111/j.1600-0854.2006.00506.x sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Multiple studies point to a role for LRRK2 at the presynaptic terminal where it plays a role in release of dopamine from striato-nigral neurons, and glutamate from corticostriatal neurons.

“Multiple studies point to a role for LRRK2 at the presynaptic terminal where it plays a role in release of dopamine from striato-nigral neurons, and glutamate from corticostriatal neurons [5, 6, 11, 50, 86, 92, 95].”

• cites [5] Beccano-Kelly DA, Kuhlmann N, Tatarnikov I, Volta M, Munsie LN, Chou P, Cao LP, Han H, Tapia L, Farrer MJ, Milnerwood AJ (2014) Synaptic function is modulated by LRRK2 and glutamate release is increased in cortical neurons of G2019S LRRK2 knock-in mice. Front Cell Neurosci 8:301. https://doi.org/10.3389/fncel.2014.00301 sourcePartly supported

  The Introduction and Discussion (pages not supplied) report that LRRK2 affects presynaptic machinery and glutamate release in cultured cortical neurons. The paper does not establish that the measured release was specifically from corticostriatal neurons, or report LRRK2-dependent dopamine release from striato-nigral neurons. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [6] Beccano-Kelly DA, Volta M, Munsie LN, Paschall SA, Tatarnikov I, Co K, Chou P, Cao LP, Bergeron S, Mitchell E et al (2015) LRRK2 overexpression alters glutamatergic presynaptic plasticity, striatal dopamine tone, postsynaptic signal transduction, motor activity and memory. Hum Mol Genet 24:1336–1349. https://doi.org/10.1093/hmg/ddu543 sourceNot checked — no full text of the source
• cites [11] Chen C, Soto G, Dumrongprechachan V, Bannon N, Kang S, Kozorovitskiy Y, Parisiadou L (2020) Pathway-specific dysregulation of striatal excitatory synapses by LRRK2 mutations. Elife 9:1. https://doi.org/10.7554/eLife.58997 sourcePartly supported

  The Introduction and Discussion report evidence that LRRK2 regulates presynaptic glutamatergic transmission, supporting the glutamate-release portion of the claim. The passages about dopamine concern dopamine loss and its effects on striatal neurons; they do not support a role for LRRK2 in dopamine release from striato-nigral neurons. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [50] Matikainen-Ankney BA, Kezunovic N, Mesias RE, Tian Y, Williams FM, Huntley GW, Benson DL (2016) Altered development of synapse structure and function in striatum caused by Parkinson’s disease-linked LRRK2-G2019S mutation. J Neurosci 36:7128–7141. https://doi.org/10.1523/JNEUROSCI.3314-15.2016 sourcePartly supported

  The Results section on corticostriatal afferents reports that elevated glutamatergic synaptic activity in G2019S mice depends on cortical input, and the Discussion suggests a possible presynaptic mechanism. The paper does not establish that LRRK2 acts at those terminals to control glutamate release, and it does not report dopamine release from striato-nigral neurons. Page numbers were not available in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [86] Volta M, Beccano-Kelly DA, Paschall SA, Cataldi S, MacIsaac SE, Kuhlmann N, Kadgien CA, Tatarnikov I, Fox J, Khinda J et al (2017) Initial elevations in glutamate and dopamine neurotransmission decline with age, as does exploratory behavior, in LRRK2 G2019S knock-in mice. Elife 6:1. https://doi.org/10.7554/eLife.28377 sourcePartly supported

  The Results sections on striatal glutamate transmission and dopamine release report altered presynaptic glutamate transmission and dopamine release in LRRK2 G2019S mice. But the paper calls the dopamine pathway nigrostriatal, not striatonigral, and says its experiments did not distinguish corticostriatal from thalamostriatal glutamate inputs. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [92] Xenias HS, Chen C, Kang S, Cherian S, Situ X, Shanmugasundaram B, Liu G, Scesa G, Savio Chan C, Parisiadou L (2022) R1441C and G2019S LRRK2 knockin mice have distinct striatal molecular, physiological, and behavioral alterations. Commun Biol 5:1211. https://doi.org/10.1038/s42003-022-04136-8 sourcePartly supported

  The Discussion reports that LRRK2 mutations affect presynaptic dopamine release, supporting the dopamine portion of the claim. The Results report no difference in a measure of presynaptic corticostriatal transmission in the R1441C mice tested, so this paper does not establish a role in glutamate release from those neurons. It also describes the dopamine pathway as nigrostriatal, rather than striato-nigral. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [95] Yue M, Hinkle KM, Davies P, Trushina E, Fiesel FC, Christenson TA, Schroeder AS, Zhang L, Bowles E, Behrouz B et al (2015) Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice. Neurobiol Dis 78:172–195. https://doi.org/10.1016/j.nbd.2015.02.031 sourcePartly supported

  The Discussion (page unavailable) reports reduced striatal dopamine release in G2019S mice and proposes impaired vesicular exocytosis; it also reports increased glutamate release in cortical cultures. It does not establish glutamate release specifically from corticostriatal neurons, and it describes the dopamine projections as nigro-striatal rather than striato-nigral. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Probably not a substantial claim. The paper’s conclusions may not depend on it.

LRRK2 activity has been demonstrated in glial cells including astrocytes, microglia and oligodendrocytes.

“LRRK2 activity has been demonstrated in glial cells including astrocytes, microglia and oligodendrocytes [30, 55, 97], identified with markers GFAP, CD68 and Olig2.”

• cites [30] Khan SS, Sobu Y, Dhekne HS, Tonelli F, Berndsen K, Alessi DR, Pfeffer SR (2021) Pathogenic LRRK2 control of primary cilia and Hedgehog signaling in neurons and astrocytes of mouse brain. Elife 10:1. https://doi.org/10.7554/eLife.67900 sourcePartly supported

  The Results section, “Phosphorylated Rab10 in astrocyte ciliogenesis” (page unavailable), reports increased phospho-Rab10 in cultured G2019S LRRK2 astrocytes and a reduction with an LRRK2 inhibitor, supporting activity in astrocytes. The paper does not demonstrate LRRK2 activity in microglia or oligodendrocytes; it identifies astrocytes with GFAP, but does not establish the cited CD68 or Olig2 marker use. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [55] Moehle MS, Webber PJ, Tse T, Sukar N, Standaert DG, DeSilva TM, Cowell RM, West AB (2012) LRRK2 inhibition attenuates microglial inflammatory responses. J Neurosci 32:1602–1611. https://doi.org/10.1523/JNEUROSCI.5601-11.2012 sourcePartly supported

  The Results section demonstrates LRRK2 activity in stimulated microglia, and the Results on TLR4-stimulated cells report LRRK2 expression in cultured astrocytes, while noting that astrocyte expression was not observed in vivo. The paper includes oligodendrocytes in a comparison of protein levels but does not demonstrate LRRK2 activity in them; expression alone also does not establish activity in astrocytes. No page numbers are available in our copy. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [97] Zaldivar-Diez J, Li L, Garcia AM, Zhao WN, Medina-Menendez C, Haggarty SJ, Gil C, Morales AV, Martinez A (2020) Benzothiazole-based LRRK2 inhibitors as wnt enhancers and promoters of oligodendrocytic fate. J Med Chem 63:2638–2655. https://doi.org/10.1021/acs.jmedchem.9b01752 sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Rab10 plays a role in axonal anterograde traffic of vesicles to the axon tip.

“In addition, Rab10 has been shown to play a role in axonal anterograde traffic of vesicles to the axon tip [14].”

• cites [14] Deng CY, Lei WL, Xu XH, Ju XC, Liu Y, Luo ZG (2014) JIP1 mediates anterograde transport of Rab10 cargos during neuronal polarization. J Neurosci 34:1710–1723. https://doi.org/10.1523/JNEUROSCI.4496-13.2014 sourceSupported

Probably not a substantial claim. It may state two separate claims as one.

Rab10 was identified as phosphorylated by LRRK2 combining two independent genetic and chemical phosphoproteomic screens and has been validated in subsequent studies.

“Rab10 specifically was identified as phosphorylated by LRRK2 combining two independent genetic and chemical phosphoproteomic screens and has been validated in subsequent studies [19, 28, 32, 34, 35, 41, 79].”

• cites [19] Fan Y, Howden AJM, Sarhan AR, Lis P, Ito G, Martinez TN, Brockmann K, Gasser T, Alessi DR, Sammler EM (2018) Interrogating Parkinson’s disease LRRK2 kinase pathway activity by assessing Rab10 phosphorylation in human neutrophils. Biochem J 475:23–44. https://doi.org/10.1042/BCJ20170803 sourcePartly supported

  The Introduction identifies Rab10 as a validated physiological substrate directly phosphorylated by LRRK2, and the Results show LRRK2-inhibitor-sensitive Rab10 phosphorylation in human neutrophils. Our copy does not say Rab10 was identified by combining two independent genetic and chemical phosphoproteomic screens; searches for that method did not establish this part of the claim. Page numbers were not available in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [28] Ito G, Katsemonova K, Tonelli F, Lis P, Baptista MA, Shpiro N, Duddy G, Wilson S, Ho PW, Ho SL et al (2016) Phos-tag analysis of Rab10 phosphorylation by LRRK2: a powerful assay for assessing kinase function and inhibitors. Biochem J 473:2671–2685. https://doi.org/10.1042/BCJ20160557 sourceSupported
• cites [32] Kuwahara T, Funakawa K, Komori T, Sakurai M, Yoshii G, Eguchi T, Fukuda M, Iwatsubo T (2020) Roles of lysosomotropic agents on LRRK2 activation and Rab10 phosphorylation. Neurobiol Dis 145:105081. https://doi.org/10.1016/j.nbd.2020.105081 sourcePartly supported

  The Introduction identifies Rab10 as an LRRK2 substrate, and the Discussion reports this paper’s own findings on LRRK2-mediated Rab10 phosphorylation. The copy does not say Rab10 was identified by combining two independent genetic and chemical phosphoproteomic screens; it cites Steger et al. (2016) for the earlier identification. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [34] Lara Ordonez AJ, Fasiczka R, Fernandez B, Naaldijk Y, Fdez E, Blanca Ramirez M, Phan S, Boassa D, Hilfiker S (2022) The LRRK2 signaling network converges on a centriolar phospho-Rab10/RILPL1 complex to cause deficits in centrosome cohesion and cell polarization. Biol Open 11:1. https://doi.org/10.1242/bio.059468 sourceSupported
• cites [35] Lara Ordonez AJ, Fernandez B, Fdez E, Romo-Lozano M, Madero-Perez J, Lobbestael E, Baekelandt V, Aiastui A, Lopez de Munain A, Melrose HL et al (2019) RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase-mediated centrosomal cohesion and ciliogenesis deficits. Hum Mol Genet 28:3552–3568. https://doi.org/10.1093/hmg/ddz201 sourceSupported
• cites [41] Lis P, Burel S, Steger M, Mann M, Brown F, Diez F, Tonelli F, Holton JL, Ho PW, Ho SL et al (2018) Development of phospho-specific Rab protein antibodies to monitor in vivo activity of the LRRK2 Parkinson’s disease kinase. Biochem J 475:1–22. https://doi.org/10.1042/BCJ20170802 sourcePartly supported

  The Introduction identifies Rab10 as an LRRK2 substrate, and the study's antibody experiments provide further evidence of LRRK2-dependent Rab10 phosphorylation. Our copy does not say Rab10 was identified by combining two independent genetic and chemical phosphoproteomic screens. The indexed passages have section labels but no page numbers. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [79] Steger M, Tonelli F, Ito G, Davies P, Trost M, Vetter M, Wachter S, Lorentzen E, Duddy G, Wilson S et al (2016) Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. Elife 5:1. https://doi.org/10.7554/eLife.12813 sourceSupported

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Microglia play a role in clearance of α-synuclein, a process regulated by LRRK2 kinase activity.

“Microglia, the resident immune cells in the brain, also play a role in clearance of α-synuclein, a process which is regulated by LRRK2 kinase activity [46, 71].”

• cites [46] Maekawa T, Sasaoka T, Azuma S, Ichikawa T, Melrose HL, Farrer MJ, Obata F (2016) Leucine-rich repeat kinase 2 (LRRK2) regulates alpha-synuclein clearance in microglia. BMC Neurosci 17:77. https://doi.org/10.1186/s12868-016-0315-2 sourcePartly supported

  The Results report that LRRK2-knockout microglia cleared more α-synuclein than wild-type microglia, supporting a role for microglia and LRRK2 in clearance. The Discussion proposes kinase activity as a possible mechanism involving Rab5 and dynamin 1, but the study tested LRRK2 knockout rather than kinase activity specifically. The claim states that mechanism more definitively than this paper establishes. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [71] Schapansky J, Nardozzi JD, LaVoie MJ (2015) The complex relationships between microglia, alpha-synuclein, and LRRK2 in Parkinson’s disease. Neuroscience 302:74–88. https://doi.org/10.1016/j.neuroscience.2014.09.049 sourcePartly supported

  The section “The clearance of extracellular αSyn by microglia” says microglia internalize α-synuclein and may help clear it. “Do Pathogenic Mutations in LRRK2 Alter The Interactions Between Microglia and αSyn?” reports that inhibiting LRRK2 kinase activity impaired microglial clearance of an aggregate-prone protein, but presents its effect on α-synuclein clearance as a possibility, not an established regulation. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In astrocytes, LRRK2 plays a role in ciliogenesis.

“In astrocytes, LRRK2 plays a role in ciliogenesis [15, 30, 35, 84].”

• cites [15] Dhekne HS, Yanatori I, Gomez RC, Tonelli F, Diez F, Schule B, Steger M, Alessi DR, Pfeffer SR (2018) A pathway for Parkinson’s Disease LRRK2 kinase to block primary cilia and Sonic hedgehog signaling in the brain. Elife 7:1. https://doi.org/10.7554/eLife.40202 sourcePartly supported

  The Results show that LRRK2 activity affects ciliogenesis in mouse embryonic fibroblasts through Rab10 and RILPL1. But the Discussion explicitly says the authors cannot yet assess astrocyte cilia in LRRK2 mutant mice and that further work is needed to determine its effects on astrocyte ciliogenesis. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [30] Khan SS, Sobu Y, Dhekne HS, Tonelli F, Berndsen K, Alessi DR, Pfeffer SR (2021) Pathogenic LRRK2 control of primary cilia and Hedgehog signaling in neurons and astrocytes of mouse brain. Elife 10:1. https://doi.org/10.7554/eLife.67900 sourceSupported
• cites [35] Lara Ordonez AJ, Fernandez B, Fdez E, Romo-Lozano M, Madero-Perez J, Lobbestael E, Baekelandt V, Aiastui A, Lopez de Munain A, Melrose HL et al (2019) RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase-mediated centrosomal cohesion and ciliogenesis deficits. Hum Mol Genet 28:3552–3568. https://doi.org/10.1093/hmg/ddz201 sourceSupported
• cites [84] Tremblay ME, Cookson MR, Civiero L (2019) Glial phagocytic clearance in Parkinson’s disease. Mol Neurodegener 14:16. https://doi.org/10.1186/s13024-019-0314-8 sourceCould not verify

  The Background section on endolysosomal dysfunction says LRRK2 affects lysosomal function in astrocytes, but does not address ciliogenesis. Searches for astrocyte ciliogenesis and primary cilia found no passage in our copy supporting that specific role; no page number is available for the section. (LLM, conf=0.72)

  Experimental — accuracy not yet measured

Probably not a substantial claim. The paper’s conclusions may not depend on it.

A variant of Rab10 was identified as potentially protective in Alzheimer's disease.

“Furthermore, a variant of Rab10 was identified as potentially protective in Alzheimer’s disease [64].”

• cites [64] Ridge PG, Karch CM, Hsu S, Arano I, Teerlink CC, Ebbert MTW, Gonzalez Murcia JD, Farnham JM, Damato AR, Allen M et al (2017) Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer’s disease resilience. Genome Med 9:100. https://doi.org/10.1186/s13073-017-0486-1 sourceSupported

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Multiple studies show that a subset of Rab GTPases are LRRK2 kinase substrates, and LRRK2 can phosphorylate these Rab GTPases in vivo and in vitro.

“Multiple studies show that a subset of Rab GTPases are LRRK2 kinase substrates, and LRRK2 can phosphorylate these Rab GTPases in vivo and in vitro [41, 79].”

• cites [41] Lis P, Burel S, Steger M, Mann M, Brown F, Diez F, Tonelli F, Holton JL, Ho PW, Ho SL et al (2018) Development of phospho-specific Rab protein antibodies to monitor in vivo activity of the LRRK2 Parkinson’s disease kinase. Biochem J 475:1–22. https://doi.org/10.1042/BCJ20170802 sourceSupported
• cites [79] Steger M, Tonelli F, Ito G, Davies P, Trost M, Vetter M, Wachter S, Lorentzen E, Duddy G, Wilson S et al (2016) Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. Elife 5:1. https://doi.org/10.7554/eLife.12813 sourceSupported

Probably not a substantial claim. The paper’s conclusions may not depend on it.

LRRK2 phosphorylated Rab10 interacts with JIP3 and JIP4 (JNK interacting proteins), scaffold proteins for JNK signaling.

“Moreover, LRRK2 phosphorylated Rab10 interacts with JIP3 and JIP4 (JNK interacting proteins), scaffold proteins for JNK signaling [89].”

• cites [89] Waschbusch D, Purlyte E, Pal P, McGrath E, Alessi DR, Khan AR (2020) Structural Basis for Rab8a Recruitment of RILPL2 via LRRK2 Phosphorylation of Switch 2. Structure 28(406–417):e406. https://doi.org/10.1016/j.str.2020.01.005 sourceSupported

Probably not a substantial claim. It may state two separate claims as one.

LRRK2 activity plays a role in synaptic vesicle endocytosis, activation of autophagy, and axonal transport of growth factor receptors.

“LRRK2 activity plays a role in synaptic vesicle endocytosis, activation of autophagy, and axonal transport of growth factor receptors [2, 7, 10, 24, 25, 36, 51, 59, 62, 75, 77, 96].”

• cites [2] Arranz AM, Delbroek L, Van Kolen K, Guimaraes MR, Mandemakers W, Daneels G, Matta S, Calafate S, Shaban H, Baatsen P et al (2015) LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism. J Cell Sci 128:541–552. https://doi.org/10.1242/jcs.158196 sourceNot checked — no full text of the source
• cites [7] Belluzzi E, Gonnelli A, Cirnaru MD, Marte A, Plotegher N, Russo I, Civiero L, Cogo S, Carrion MP, Franchin C et al (2016) LRRK2 phosphorylates pre-synaptic N-ethylmaleimide sensitive fusion (NSF) protein enhancing its ATPase activity and SNARE complex disassembling rate. Mol Neurodegener 11:1. https://doi.org/10.1186/s13024-015-0066-z sourcePartly supported

  The Background and Discussion link LRRK2 kinase activity to synaptic-vesicle exo/endocytosis, and the Results describe effects on vesicle recycling. Our copy does not support the other attributed roles—activation of autophagy or axonal transport of growth factor receptors (searched both phrases). (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [10] Brzozowski CF, Hijaz BA, Singh V, Gcwensa NZ, Kelly K, Boyden ES, West AB, Sarkar D, Volpicelli-Daley LA (2021) Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of alpha-synuclein. Acta Neuropathol Commun 9:180. https://doi.org/10.1186/s40478-021-01283-7 sourcePartly supported

  The Introduction says LRRK2 plays a role in presynaptic vesicle traffic, and the References include a study specifically on LRRK2-dependent synaptic vesicle endocytosis. The Discussion describes effects of overactive LRRK2 on autophagosome transport, but does not establish a role in activating autophagy. The paper discusses axonal transport of α-synuclein, not growth factor receptors. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [24] Heaton GR, Landeck N, Mamais A, Nalls MA, Nixon-Abell J, Kumaran R, Beilina A, Pellegrini L, Li Y, International Parkinson Disease Genomics Cet al (2020) Sequential screening nominates the Parkinson's disease associated kinase LRRK2 as a regulator of Clathrin-mediated endocytosis. Neurobiol Dis 141:104948. https://doi.org/10.1016/j.nbd.2020.104948 sourcePartly supported

  The Results report reduced synaptic endocytosis in neurons carrying an LRRK2 mutation, supporting a role in synaptic vesicle endocytosis. The Discussion mentions altered autophagic activity in LRRK2-knockout kidneys and trafficking of EGFR, but does not establish activation of autophagy or axonal transport of growth factor receptors. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [25] Hernandez-Diaz S, Ghimire S, Sanchez-Mirasierra I, Montecinos-Oliva C, Swerts J, Kuenen S, Verstreken P, Soukup SF (2022) Endophilin-B regulates autophagy during synapse development and neurodegeneration. Neurobiol Dis 163:105595. https://doi.org/10.1016/j.nbd.2021.105595 sourcePartly supported

  Section 3.4 reports that kinase-active LRRK2 G2019S increases autophagosomes at Drosophila synapses, supporting a role in autophagy. The References list studies on LRRK2 and synaptic endocytosis, but this paper does not itself establish that part of the claim. No passage found supports a role in axonal transport of growth factor receptors. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [36] Lazo OM, Schiavo G (2023) Rab10 regulates the sorting of internalised TrkB for retrograde axonal transport. Elife 12:1. https://doi.org/10.7554/eLife.81532 sourcePartly supported

  The Discussion links LRRK2 activity to Rab10 phosphorylation and discusses possible effects on the axonal trafficking of TrkB, a growth factor receptor, but says the relevant transport mechanism remains under investigation. A reference title mentions LRRK2 in synaptic endocytosis; the paper's discussion does not establish the synaptic-vesicle claim, and the supplied passages do not support the autophagy claim. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [51] Matta S, Van Kolen K, da Cunha R, van den Bogaart G, Mandemakers W, Miskiewicz K, De Bock PJ, Morais VA, Vilain S, Haddad D et al (2012) LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis. Neuron 75:1008–1021. https://doi.org/10.1016/j.neuron.2012.08.022 sourcePartly supported

  The Introduction (page unavailable) reports that changes in LRRK2 kinase activity inhibit synaptic endocytosis, supporting the synaptic-vesicle endocytosis part of the claim. Our copy does not establish that LRRK2 activates autophagy or controls axonal transport of growth factor receptors; searches for those terms returned no supporting passage. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [59] Pan PY, Li X, Wang J, Powell J, Wang Q, Zhang Y, Chen Z, Wicinski B, Hof P, Ryan TA, Yue Z (2017) Parkinson’s Disease-Associated LRRK2 Hyperactive Kinase Mutant Disrupts Synaptic Vesicle Trafficking in Ventral Midbrain Neurons. J Neurosci 37:11366–11376. https://doi.org/10.1523/JNEUROSCI.0964-17.2017 sourceNot checked — no full text of the source
• cites [62] Piccoli G, Onofri F, Cirnaru MD, Kaiser CJ, Jagtap P, Kastenmuller A, Pischedda F, Marte A, von Zweydorf F, Vogt A et al (2014) Leucine-rich repeat kinase 2 binds to neuronal vesicles through protein interactions mediated by its C-terminal WD40 domain. Mol Cell Biol 34:2147–2161. https://doi.org/10.1128/MCB.00914-13 sourcePartly supported

  The section on LRRK2 WD40 neurotoxicity reports an exoendocytotic assay in which WD40 overexpression reduced synaptotagmin uptake, supporting a role in synaptic vesicle cycling. The Discussion also links LRRK2 to vesicle trafficking. The passages found do not support the additional claims about activation of autophagy or axonal transport of growth factor receptors. Page numbers were not available in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [75] Soukup SF, Kuenen S, Vanhauwaert R, Manetsberger J, Hernandez-Diaz S, Swerts J, Schoovaerts N, Vilain S, Gounko NV, Vints K et al (2016) A LRRK2-dependent endophilina phosphoswitch is critical for macroautophagy at presynaptic terminals. Neuron 92:829–844. https://doi.org/10.1016/j.neuron.2016.09.037 sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Phosphorylation of Rab10 inhibits its interaction with EHBP1L1 and interferes with EHBP1L1 mediated recycling.

“Another study shows that phosphorylation of Rab10 inhibits its interaction of EHBP1L1 and interferes with EHBP1L1 mediated recycling [44].”

• cites [44] Liu Z, Xu E, Zhao HT, Cole T, West AB (2020) LRRK2 and Rab10 coordinate macropinocytosis to mediate immunological responses in phagocytes. EMBO J 39:e104862. https://doi.org/10.15252/embj.2020104862 sourceSupported

It may state two separate claims as one.

The pRab10 antibody specificity was assessed by Rab10 knock down experiments in the brain in vivo and Rab10 KO iNs.

“To assess specificity of the pRab10 antibody we performed Rab10 knock down experiments in the brain in vivo and utilized Rab10 KO iNs [47].”

• cites [47] Mamais A, Sanyal A, Fajfer A, Zykoski CG, Guldin M, Riley-DiPaolo A, Subrahmanian N, Gibbs W, Lin S, LaVoie MJ (2023) The LRRK2 kinase substrates Rab8a and Rab10 contribute complementary but distinct disease-relevant phenotypes in human neurons. bioRxiv. https://doi.org/10.1101/2023.04.30.538317 sourceSupported

It may state two separate claims as one.

Rab10 colocalizes with endoplasmic reticulum, Golgi/trans-Golgi network, and lysosome/late endosome markers.

“While Rab10 colocalized with endoplasmic reticulum, lysosome and trans-Golgi network markers”

• Also stated in: § Introduction · plain

  “At a subcellular level, Rab10 localized to the ER, Golgi, and late endosomes”

It may state two separate claims as one.

Both Rab10 and pRab10 were expressed in the SNc.

“Low magnification images show that both Rab10 and pRab10 were expressed in the SNc (Fig. 4a, c).”

It may state two separate claims as one.

Rab10 levels were reduced in the cortex (p=0.002), midbrain (p=0.04), and striatum (p=0.06) in Rab10 ASO1 injected mice compared to control ASO injected mice.

“Quantification of Rab10 immunoblots showed significant reductions of Rab10 in the cortex (p value = 0.002), midbrain (p value = 0.04), and in the striatum (p value = 0.06) (Fig. 1b).”

It may state two separate claims as one.

pRab10 levels were significantly reduced in the cortex (p=0.004), midbrain (p=0.002), and striatum (p=0.004) in Rab10 ASO1 injected mice compared to control ASO injected mice.

“Similarly, pRab10 levels were significantly reduced in the cortex (p value = 0.004), midbrain (p value = 0.002), and in the striatum (p value = 0.004) in Rab10 ASO1 injected mice compared to control ASO injected mice (Fig. 1d).”

It may state two separate claims as one.

pRab10 does not localize to endoplasmic reticulum, Golgi, or lysosome/late endosome markers.

“pRab10 did not localize to these organelles.”

• Also stated in: § Introduction · plain

  “while pT73Rab10 did not overlap with markers of these organelles.”

It may state two separate claims as one.

Rab10 and pRab10 did not colocalize with early endosome marker EEA1 (MCC = 0.0003 for Rab10/EEA1, MCC = 0.0002 for pRab10/EEA1; no significant difference, p = 0.4).

“Rab10 and pRab10 did not colocalize with early endosome marker, EEA1 (Fig. 6j, k) with MCC = 0.0003 for Rab10/EEA1, and MCC = 0.0002 for pRab10/EEA1. There was no significant difference between MCC values (p = 0.4) (Fig. 6l).”

It may state two separate claims as one.

Rab10 and pRab10 are expressed in the cortex, striatum, and substantia nigra pars compacta/midbrain.

“Rab10 and pRab10 were expressed in the cortex, striatum and the substantia nigra pars compacta.”

• Also stated in: § Introduction · plain

  “We found Rab10 and pRab10 localized to most neuron and glial cell types in the cortex, striatum and midbrain.”

It may state two separate claims as one.

Rab10 overlapped with both VAMP2 and Homer1.

“Immunofluorescence showed that Rab10 overlapped with both VAMP2 and Homer1 (Fig. 7a).”

It may state two separate claims as one.

Rab10 and pRab10 are in close proximity with α-synuclein as 0.0361 μm and 0.0347 μm respectively.

“Quantitation of distance measurement indicates that Rab10 and pRab10 are in close proximity with α-synuclein as 0.0361 µm and 0.0347 µm respectively (Fig. 7g).”

It may state two separate claims as one.

In human brain temporal cortex, pRab10 showed overlap with presynaptic marker VAMP2 but not with Homer1.

“pRab10 showed overlap with presynaptic marker VAMP2 but not with Homer1, a postsynaptic marker (Fig. 7h).”

It may state two separate claims as one.

pRab10 mainly localized with presynaptic marker VAMP2, but not with postsynaptic marker Homer1.

“Interestingly, pRab10 mainly localized with presynaptic marker VAMP2, but not with the postsynaptic marker Homer1 (Fig. 7c).”

The quote only partly states this claim.

The pRab10 antibody (ab241060) is specific for pRab10 in immunofluorescence.

“To confirm the specificity of the pRab10 antibody (ab241060, Abcam), recommended for immunofluorescence, a separate cohort of C57BL/6J mice were injected intracerebroventricularly with Rab10 ASO1 and control ASO for immunofluorescence experiments.”

• Also stated in: § Validation of Rab10 and pRab10 antibodies in mouse brain · plain

  “In the Rab10 KO iNs, although there was some signal, in any given area of the confocal image, the signal in Rab10 KO was far less compared to WT cells (Additional file 2 a, b).”

• AssumptionRests on an assumption: The Rab10 knockout human induced neurons lack Rab10.

Probably not a substantial claim.

LRRK2 is expressed in striatal spiny projection neurons (SPNs).

“A previous study from our lab showed that LRRK2 is expressed in striatal spiny projection neurons (SPNs) which comprise 95 to 98% of neurons in the striatum [22, 56].”

• cites [22] Gustafson EL, Ehrlich ME, Trivedi P, Greengard P (1992) Developmental regulation of phosphoprotein gene expression in the caudate-putamen of rat: an in situ hybridization study. Neuroscience 51:65–75. https://doi.org/10.1016/0306-4522(92)90471-d sourceNot checked — no full text of the source
• cites [56] Ouimet CC, Langley-Gullion KC, Greengard P (1998) Quantitative immunocytochemistry of DARPP-32-expressing neurons in the rat caudatoputamen. Brain Res 808:8–12. https://doi.org/10.1016/s0006-8993(98)00724-0 sourceNot checked — no full text of the source

It may state two separate claims as one. The quote only partly states this claim.

Rab10 ASO treatment specifically reduces Rab10 without reducing Rab8a in primary corticostriatal neurons.

“To further confirm the Rab10 ASO specificity, primary corticostriatal neurons were treated with control and Rab10 ASOs as described in the methods section.”

• Also stated in: § Validation of Rab10 and pRab10 antibodies in mouse brain · plain

  “The statistical analysis using unpaired t-test with Welch’s correction shows no significant difference in the Rab8a level in the control ASO and Rab10 ASO treated samples (p value = 0.56).”

It may state two separate claims as one.

Rab10 and pRab10 are expressed in all brain areas and cell types tested in this study, but pRab10 is enriched at the presynaptic terminal.

“Results from this study suggest Rab10 and pRab10 are expressed in all brain areas and cell types tested in this study, but pRab10 is enriched at the presynaptic terminal.”

Probably not a substantial claim.

Autosomal dominant pathogenic mutations in LRRK2 cause Parkinson's disease.

“Autosomal dominant pathogenic mutations in Leucine-rich repeat kinase 2 (LRRK2) cause Parkinson’s disease (PD).”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Mutations in LRRK2 are the most common genetic cause of Parkinson's disease.

“Mutations in the LRRK2 gene are the most common genetic cause of PD.”

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

LRRK2 localizes to and plays a role in synaptic vesicle trafficking.

“LRRK2 localizes to and plays a role in synaptic vesicle trafficking [2, 10, 13, 49].”

• cites [2] Arranz AM, Delbroek L, Van Kolen K, Guimaraes MR, Mandemakers W, Daneels G, Matta S, Calafate S, Shaban H, Baatsen P et al (2015) LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism. J Cell Sci 128:541–552. https://doi.org/10.1242/jcs.158196 sourceNot checked — no full text of the source
• cites [10] Brzozowski CF, Hijaz BA, Singh V, Gcwensa NZ, Kelly K, Boyden ES, West AB, Sarkar D, Volpicelli-Daley LA (2021) Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of alpha-synuclein. Acta Neuropathol Commun 9:180. https://doi.org/10.1186/s40478-021-01283-7 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

• cites [13] Cirnaru MD, Marte A, Belluzzi E, Russo I, Gabrielli M, Longo F, Arcuri L, Murru L, Bubacco L, Matteoli M et al (2014) LRRK2 kinase activity regulates synaptic vesicle trafficking and neurotransmitter release through modulation of LRRK2 macro-molecular complex. Front Mol Neurosci 7:49. https://doi.org/10.3389/fnmol.2014.00049 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

• cites [49] Matikainen-Ankney BA, Kezunovic N, Menard C, Flanigan ME, Zhong Y, Russo SJ, Benson DL, Huntley GW (2018) Parkinson’s disease-linked LRRK2-G2019S mutation alters synaptic plasticity and promotes resilience to chronic social stress in young adulthood. J Neurosci 38:9700–9711. https://doi.org/10.1523/JNEUROSCI.1457-18.2018 sourceNot checked yet

  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.

Phosphorylation not only interferes with the interaction of Rabs with its effector proteins, but in a few cases facilitates alternative interactions of Rabs with a completely new effector protein when they are phosphorylated.

“Studies show that phosphorylation not only interferes with the interaction of Rabs with its effector proteins, but in a few cases facilitates alternative interactions of Rabs with a completely new effector protein when they are phosphorylated [78].”

• cites [78] Steger M, Diez F, Dhekne HS, Lis P, Nirujogi RS, Karayel O, Tonelli F, Martinez TN, Lorentzen E, Pfeffer SR et al (2017) Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis. Elife 6:1. https://doi.org/10.7554/eLife.31012 sourceNot checked yet

  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.

This process can reduce the pathological burden by clearing misfolded proteins including α-synuclein, tau and other cellular debris.

“This process can reduce the pathological burden by clearing misfolded proteins including α-synuclein, tau and other cellular debris.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Rab10 has been shown to be involved in micropinocytosis, the process of internalizing small and soluble substances, that occurs in macrophages.

“Recently, Rab10 has been shown to be involved in micropinocytosis, the process of internalizing small and soluble substances, that occurs in macrophages [44].”

• cites [44] Liu Z, Xu E, Zhao HT, Cole T, West AB (2020) LRRK2 and Rab10 coordinate macropinocytosis to mediate immunological responses in phagocytes. EMBO J 39:e104862. https://doi.org/10.15252/embj.2020104862 sourceNot checked yet

Probably not a substantial claim. The paper’s conclusions may not depend on it.

LRRK2 phosphorylation of Rab10 may impact oligodendrocyte development and myelination in the central nervous system.

“Finally, Rab10 has been implicated in oligodendrocyte maturation [98] and LRRK2 phosphorylation of Rab10 may impact oligodendrocyte development and myelination in the central nervous system.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Cargo adaptor proteins from the RILP family (RILPL1 and RILPL2) involved in ciliogenesis bind tightly with some phosphorylated Rabs including Rab10, but not with unphosphorylated Rabs.

“For example, cargo adaptor proteins from the RILP (Rab interacting lysosomal protein like) family (RILPL1 and RILPL2) involved in ciliogenesis, bind tightly with some of the phosphorylated Rabs including Rab10, but not with the unphosphorylated Rabs [35, 78].”

• cites [35] Lara Ordonez AJ, Fernandez B, Fdez E, Romo-Lozano M, Madero-Perez J, Lobbestael E, Baekelandt V, Aiastui A, Lopez de Munain A, Melrose HL et al (2019) RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase-mediated centrosomal cohesion and ciliogenesis deficits. Hum Mol Genet 28:3552–3568. https://doi.org/10.1093/hmg/ddz201 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

• cites [78] Steger M, Diez F, Dhekne HS, Lis P, Nirujogi RS, Karayel O, Tonelli F, Martinez TN, Lorentzen E, Pfeffer SR et al (2017) Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis. Elife 6:1. https://doi.org/10.7554/eLife.31012 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

It may state two separate claims as one.

At the presynaptic terminal, PPMIH activity is limited and LRRK2-mediated phosphorylation of Rab10 is important for synaptic function.

“At the presynaptic terminal however, our findings suggest that PPMIH activity is limited and that LRRK2-mediated phosphorylation of Rab10 is important for synaptic function.”

It may state two separate claims as one.

The presence of Rab10 and pRab10 in the SNc and its enrichment in TH and DAT neurons indicate that it can play a role in these cells.

“The presence of Rab10 and pRab10 in the SNc and its enrichment in TH and DAT neurons indicate that it can play a role in these cells, which is important because loss of dopamine neurons is responsible for some of the motor symptoms in PD.”

• AssumptionRests on an assumption: Dopaminergic cell loss in the SNc is a hallmark of PD pathology.
• AssumptionRests on an assumption: Mutant LRRK2 causes PD.
• AssumptionRests on an assumption: Loss of dopamine neurons is responsible for some of the motor symptoms in PD.

It may state two separate claims as one.

pRab10 localization and its distance measurement at the synapse in human brain samples were similar to the results from mouse brain cortex.

“Interestingly, pRab10 localization and its distance measurement at the synapse in the human brain samples were similar to the results from the mouse brain cortex.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Rab10 has been implicated in oligodendrocyte maturation.

“Finally, Rab10 has been implicated in oligodendrocyte maturation [98] and LRRK2 phosphorylation of Rab10 may impact oligodendrocyte development and myelination in the central nervous system.”

• cites [98] Zhang ZH, Zhao WQ, Ma FF, Zhang H, Xu XH (2017) Rab10 Disruption Results in Delayed OPC Maturation. Cell Mol Neurobiol 37:1303–1310. https://doi.org/10.1007/s10571-017-0465-5 sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

In the context of increased LRRK2 activity in PD, aberrations in these functions could lead to reduced availability of synaptic vesicles for neurotransmission, accumulation of damaged proteins and organelles and impaired transport of growth factor signaling to the cell body; all of which could result in neurodegeneration.

“In the context of increased LRRK2 activity in PD, aberrations in these functions could lead to reduced availability of synaptic vesicles for neurotransmission, accumulation of damaged proteins and organelles and impaired transport of growth factor signaling to the cell body; all of which could result in neurodegeneration.”