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RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase–mediated centrosomal cohesion and ciliogenesis deficits

Lara Ordónez, Antonio Jesús, Fernández, Belén, Fdez, Elena, Romo-Lozano, María, Madero-Pérez, Jesús, Lobbestael, Evy, Baekelandt, Veerle, Aiastui, Ana, López de Munaín, Adolfo, Melrose, Heather L, Civiero, Laura, Hilfiker, Sabine·2019·Human Molecular Genetics
DOI 10.1093/hmg/ddz201PMC PMC6927464
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Abstract

Mutations in the LRRK2 kinase are the most common cause of familial Parkinson’s disease, and variants increase risk for the sporadic form of the disease. LRRK2 phosphorylates multiple RAB GTPases including RAB8A and RAB10. Phosphorylated RAB10 is recruited to centrosome-localized RILPL1, which may interfere with ciliogenesis in a disease-relevant context. Our previous studies indicate that the centrosomal accumulation of phosphorylated RAB8A causes centrosomal cohesion deficits in dividing cells, including in peripheral patient-derived cells. Here, we show that both RAB8 and RAB10 contribute to the centrosomal cohesion deficits. Pathogenic LRRK2 causes the centrosomal accumulation not only of phosho-RAB8 but also of phospho-RAB10, and the effects on centrosomal cohesion are dependent on RAB8, RAB10 and RILPL1. Conversely, the pathogenic LRRK2-mediated ciliogenesis defects correlate with the centrosomal accumulation of both phospho-RAB8 and phospho-RAB10. LRRK2-mediated centrosomal cohesion and ciliogenesis alterations are observed in patient-derived peripheral cells, as well as in primary astrocytes from mutant LRRK2 mice, and are reverted upon LRRK2 kinase inhibition. These data suggest that the LRRK2-mediated centrosomal cohesion and ciliogenesis defects are distinct cellular readouts of the same underlying phospho-RAB8/RAB10/RILPL1 nexus and highlight the possibility that either centrosomal cohesion and/or ciliogenesis alterations may serve as cellular biomarkers for LRRK2-related PD.

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  • 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].”

    From Cellular and subcellular localization of Rab10 and phospho-T73 Rab10 in the mouse and human brain (2023) · cites this paper as [35]

  • In astrocytes, LRRK2 plays a role in ciliogenesis.

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

    From Cellular and subcellular localization of Rab10 and phospho-T73 Rab10 in the mouse and human brain (2023) · cites this paper as [35]

  • Most 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].”

    From Distinct Roles for RAB10 and RAB29 in Pathogenic LRRK2-Mediated Endolysosomal Trafficking Alterations (2020) · cites this paper as [39]

    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

  • 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].”

    From Cellular and subcellular localization of Rab10 and phospho-T73 Rab10 in the mouse and human brain (2023) · cites this paper as [35]

  • RAB10 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].”

    From Distinct Roles for RAB10 and RAB29 in Pathogenic LRRK2-Mediated Endolysosomal Trafficking Alterations (2020) · cites this paper as [39]

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Citations

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Research works printed but not linked: 44

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Metadata

Authors
Lara Ordónez, A. J., Fernández, B., Fdez, E., Romo-Lozano, M., Madero-Pérez, J., Lobbestael, E., Baekelandt, V., Aiastui, A., López de Munaín, A., Melrose, H. L., Civiero, L., & Hilfiker, S.
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2019-08-20
Volume
28
Issue
21
Pages
3552-3568
ISSN
  • 0964-6906
  • 1460-2083
DOI
10.1093/hmg/ddz201
PMC
PMC6927464
Cited by
103
References
8
Language
en
Licence
creativecommons.org/licenses/by-nc/4.0/ (vor)
Funders
  • European Regional Development Fund
  • Spanish Ministry of Economy and Competitiveness (SAF2017-89402-R)
  • Spanish Ministry of Education, Culture and Sport (FPU15/05233)

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