title: LRRK2 and Parkinson's Disease: From Lack of Structure to Gain of Function.
abstract: Mutations in LRRK2 comprise the most common cause for familial Parkinson's disease (PD), and variations increase risk for sporadic disease, implicating LRRK2 in the entire disease spectrum. LRRK2 is a large protein harbouring both GTPase and kinase domains which display measurable catalytic activity. Most pathogenic mutations increase the kinase activity, with increased activity being cytotoxic under certain conditions. These findings have spurred great interest in drug development approaches, and various specific LRRK2 kinase inhibitors have been developed. However, LRRK2 is a largely ubiquitously expressed protein, and inhibiting its function in some non-neuronal tissues has raised safety liability issues for kinase inhibitor approaches. Therefore, understanding the cellular and cell type-specific role(s) of LRRK2 has become of paramount importance. This review will highlight current knowledge on the precise biochemical activities of normal and pathogenic LRRK2, and highlight the most common proposed cellular roles so as to gain a better understanding of the cell type-specific effects of LRRK2 modulators.
authors.affiliation: Institute of Parasitology and Biomedicine "Lopez-Neyra", Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain.
authors.forename: Marian
authors.initials: M
authors.lastname: Blanca Ramírez
authors.affiliation: Institute of Parasitology and Biomedicine "Lopez-Neyra", Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Madero-Perez
authors.affiliation: Institute of Parasitology and Biomedicine "Lopez-Neyra", Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Rivero-Rios
authors.affiliation: Institute of Parasitology and Biomedicine "Lopez-Neyra", Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Martinez-Salvador
authors.affiliation: Institute of Parasitology and Biomedicine "Lopez-Neyra", Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain.
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Lara Ordonez
authors.affiliation: Institute of Parasitology and Biomedicine "Lopez-Neyra", Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain.
authors.forename: Belen
authors.initials: B
authors.lastname: Fernandez
authors.affiliation: Institute of Parasitology and Biomedicine "Lopez-Neyra", Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Fdez
authors.affiliation: Institute of Parasitology and Biomedicine "Lopez-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: D000631:Aminopyridines / Q000494:pharmacology; D000978:Antiparkinson Agents / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D001549:Benzamides / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects; D015870:Gene Expression; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000072417:Protein Domains; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020761:rab1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: D000631:Aminopyridines; D000978:Antiparkinson Agents; D001549:Benzamides; C000600930:GSK2578215A; D047428:Protein Kinase Inhibitors; C000598762:Rab29 protein, human; D051844:alpha-Synuclein; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D020691:rab GTP-Binding Proteins; D020761:rab1 GTP-Binding Proteins
keywords: Autophagy; GTPase; LRRK2; Parkinson's disease; Rab7; Rab7L1; endocytosis; kinase