Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene comprise the most common cause of familial Parkinson's disease (PD), and variants increase the risk for sporadic PD. LRRK2 displays kinase and GTPase activity, and altered catalytic activity correlates with neurotoxicity, making LRRK2 a promising therapeutic target. Despite the importance of LRRK2 for disease pathogenesis, its normal cellular function, and the mechanism(s) by which pathogenic mutations cause neurodegeneration remain unclear. LRRK2 seems to regulate a variety of intracellular vesicular trafficking events to and from the late endosome in a manner dependent on various Rab proteins. At least some of those events are further regulated by LRRK2 in a manner dependent on two-pore channels (TPCs). TPCs are ionic channels localized to distinct endosomal structures and can cause localized calcium release from those acidic stores, with downstream effects on vesicular trafficking. Here, we review current knowledge about the link between LRRK2, TPC- and Rab-mediated vesicular trafficking to and from the late endosome, highlighting a possible cross-talk between endolysosomal calcium stores and Rab proteins underlying pathomechanism(s) in LRRK2-related PD.
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June 2015
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Conference Article|
June 01 2015
Alterations in late endocytic trafficking related to the pathobiology of LRRK2-linked Parkinson's disease
Pilar Rivero-Ríos;
Pilar Rivero-Ríos
*Institute of Parasitology and Biomedicine “López-Neyra”, Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain
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Patricia Gómez-Suaga;
Patricia Gómez-Suaga
*Institute of Parasitology and Biomedicine “López-Neyra”, Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain
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Belén Fernández;
Belén Fernández
*Institute of Parasitology and Biomedicine “López-Neyra”, Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain
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Jesús Madero-Pérez;
Jesús Madero-Pérez
*Institute of Parasitology and Biomedicine “López-Neyra”, Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain
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Andrew J. Schwab;
Andrew J. Schwab
†Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, U.S.A.
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Allison D. Ebert;
Allison D. Ebert
†Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, U.S.A.
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Sabine Hilfiker
Sabine Hilfiker
1
*Institute of Parasitology and Biomedicine “López-Neyra”, Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain
1To whom correspondence should be addressed (emailsabine.hilfiker@ipb.csic.es).
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Publisher: Portland Press Ltd
Received:
November 12 2014
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2015 Biochemical Society
2015
Biochem Soc Trans (2015) 43 (3): 390–395.
Article history
Received:
November 12 2014
Citation
Pilar Rivero-Ríos, Patricia Gómez-Suaga, Belén Fernández, Jesús Madero-Pérez, Andrew J. Schwab, Allison D. Ebert, Sabine Hilfiker; Alterations in late endocytic trafficking related to the pathobiology of LRRK2-linked Parkinson's disease. Biochem Soc Trans 1 June 2015; 43 (3): 390–395. doi: https://doi.org/10.1042/BST20140301
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