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LRRK2 delays degradative receptor trafficking by impeding late endosomal budding through decreasing Rab7 activity

Gómez-Suaga, Patricia, Rivero-Ríos, Pilar, Fdez, Elena, Blanca Ramírez, Marian, Ferrer, Isidro, Aiastui, Ana, López De Munain, Adolfo, Hilfiker, Sabine·2014·Human Molecular Genetics
DOI 10.1093/hmg/ddu395
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Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset autosomal dominant Parkinson's disease (PD), and sequence variations at the LRRK2 locus are associated with increased risk for sporadic PD. LRRK2 contains both GTPase and kinase domains flanked by protein interaction motifs, and mutations associated with familial PD have been described for both catalytic domains. LRRK2 has been implicated in diverse cellular processes, and recent evidence pinpoints to an important role for LRRK2 in modulating a variety of intracellular membrane trafficking pathways. However, the underlying mechanisms are poorly understood. Here, by studying the classical, well-understood, degradative trafficking pathway of the epidermal growth factor receptor (EGFR), we show that LRRK2 regulates endocytic membrane trafficking in an Rab7-dependent manner. Mutant LRRK2 expression causes a slight delay in early-to-late endosomal trafficking, and a pronounced delay in trafficking out of late endosomes, which become aberrantly elongated into tubules. This is accompanied by a delay in EGFR degradation. The LRRK2-mediated deficits in EGFR trafficking and degradation can be reverted upon coexpression of active Rab7 and of a series of proteins involved in bridging the EGFR to Rab7 on late endosomes. Effector pulldown assays indicate that pathogenic LRRK2 decreases Rab7 activity both in cells overexpressing LRRK2, as well as in fibroblasts from pathogenic mutant LRRK2 PD patients when compared…

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  • The 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].”

    From Distinct Roles for RAB10 and RAB29 in Pathogenic LRRK2-Mediated Endolysosomal Trafficking Alterations (2020) · cites this paper as [30]

  • Pathogenic 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].”

    From Distinct Roles for RAB10 and RAB29 in Pathogenic LRRK2-Mediated Endolysosomal Trafficking Alterations (2020) · cites this paper as [30]

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Metadata

Authors
Gómez-Suaga, P., Rivero-Ríos, P., Fdez, E., Blanca Ramírez, M., Ferrer, I., Aiastui, A., López De Munain, A., & Hilfiker, S.
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2014-07-30
Volume
23
Issue
25
Pages
6779-6796
ISSN
  • 1460-2083
  • 0964-6906
DOI
10.1093/hmg/ddu395
Cited by
140
References
3
Language
en

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