title: Alterations in late endocytic trafficking related to the pathobiology of LRRK2-linked Parkinson's disease.
abstract: 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.
authors.affiliation: *Institute of Parasitology and Biomedicine "López-Neyra", Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Rivero-Ríos
authors.affiliation: *Institute of Parasitology and Biomedicine "López-Neyra", Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Gómez-Suaga
authors.affiliation: *Institute of Parasitology and Biomedicine "López-Neyra", Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Fernández
authors.affiliation: *Institute of Parasitology and Biomedicine "López-Neyra", Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Madero-Pérez
authors.affiliation: †Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, U.S.A.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Schwab
authors.affiliation: †Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, U.S.A.
authors.forename: Allison D
authors.initials: AD
authors.lastname: Ebert
authors.affiliation: *Institute of Parasitology and Biomedicine "López-Neyra", Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hilfiker
mesh_terms: D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004705:Endocytosis / Q000235:genetics*; D011992:Endosomes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D016601:RNA-Binding Proteins; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases