title: LRRK2: from kinase to GTPase to microtubules and back.
abstract: Mutations in theLeucine-Rich Repeat Kinase 2(LRRK2) gene are intimately linked to both familial and sporadic Parkinson's disease. LRRK2 is a large protein kinase able to bind and hydrolyse GTP. A wealth ofin vitrostudies have established that the distinct pathogenic LRRK2 mutants differentially affect those enzymatic activities, either causing an increase in kinase activity without altering GTP binding/GTP hydrolysis, or displaying no change in kinase activity but increased GTP binding/decreased GTP hydrolysis. Importantly, recent studies have shown that all pathogenic LRRK2 mutants display increased kinase activity towards select kinase substrates when analysed in intact cells. To understand those apparently discrepant results, better insight into the cellular role(s) of normal and pathogenic LRRK2 is crucial. Various studies indicate that LRRK2 regulates numerous intracellular vesicular trafficking pathways, but the mechanism(s) by which the distinct pathogenic mutants may equally interfere with such pathways has largely remained elusive. Here, we summarize the known alterations in the catalytic activities of the distinct pathogenic LRRK2 mutants and propose a testable working hypothesis by which the various mutants may affect membrane trafficking events in identical ways by culminating in increased phosphorylation of select substrate proteins known to be crucial for membrane trafficking between specific cellular compartments.
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: Marian
authors.initials: M
authors.lastname: Blanca Ramírez
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: Antonio Jesús
authors.initials: AJ
authors.lastname: Lara Ordóñez
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: Elena
authors.initials: E
authors.lastname: Fdez
authors.affiliation: Institute of Parasitology and Biomedicine 'López-Neyra', Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain sabine.hilfiker@ipb.csic.es.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hilfiker
mesh_terms: D000818:Animals; D055162:Biocatalysis; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D020558:GTP Phosphohydrolases
keywords: Parkinson's disease; Rab protein; leucine-rich repeat kinase; microtubule; phosphorylation; vesicle transport