Mutations in the Leucine-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 of in vitro studies 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.
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February 2017
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Cover Image
Cover Image
The surface of the catalytic subunit of protein phosphatase PP1 (central 3D-structure) has many binding sites for regulatory proteins that are embedded in regulatory networks (coloured circles linked by lines). Please see pp. 89–99 for more information. Image provided by Mathieu Bollen.
Review Article|
February 15 2017
LRRK2: from kinase to GTPase to microtubules and back
Marian Blanca Ramírez;
Marian Blanca Ramírez
1Institute of Parasitology and Biomedicine ‘López-Neyra’, Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain
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Antonio Jesús Lara Ordóñez;
Antonio Jesús Lara Ordóñez
1Institute of Parasitology and Biomedicine ‘López-Neyra’, Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain
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Elena Fdez;
Elena Fdez
1Institute of Parasitology and Biomedicine ‘López-Neyra’, Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain
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Sabine Hilfiker
1Institute of Parasitology and Biomedicine ‘López-Neyra’, Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain
Correspondence: Sabine Hilfiker (sabine.hilfiker@ipb.csic.es)
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Biochem Soc Trans (2017) 45 (1): 141–146.
Article history
Received:
September 16 2016
Revision Received:
October 14 2016
Accepted:
October 18 2016
Citation
Marian Blanca Ramírez, Antonio Jesús Lara Ordóñez, Elena Fdez, Sabine Hilfiker; LRRK2: from kinase to GTPase to microtubules and back. Biochem Soc Trans 8 February 2017; 45 (1): 141–146. doi: https://doi.org/10.1042/BST20160333
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