Title: Identification of protein phosphatase 1 as a regulator of the LRRK2 phosphorylation cycle
Authors: Lobbestael, Evy ×
Zhao, Jing
Rudenko, Iakov N
Beylina, Aleksandra
Gao, Fangye
Wetter, Justin
Beullens, Monique
Bollen, Mathieu
Cookson, Mark R
Baekelandt, Veerle
Nichols, R Jeremy
Taymans, Jean-Marc #
Issue Date: Nov-2013
Publisher: Published by Portland Press on behalf of the Biochemical Society
Series Title: Biochemical Journal vol:456 issue:1 pages:119-128
Abstract: A cluster of phosphorylation sites in LRRK2 (leucine-rich repeat kinase 2), including serines 910, 935, 955 and 973, is important for Parkinson's disease (PD) pathogenesis as several PD-linked LRRK2 mutants are dephosphorylated at these sites. LRRK2 is also dephosphorylated in cells after pharmacological inhibition of its kinase activity, which is currently proposed as a strategy for disease-modifying PD therapy. Despite this importance of LRRK2 dephosphorylation in mutant LRRK2 pathological mechanism(s) and in LRRK2's response to inhibition, the mechanism by which this occurs is unknown. Therefore, we aimed to identify the phosphatase for LRRK2. Using a panel of recombinant phosphatases we find that protein phosphatase 1 (PP1) efficiently dephosphorylates LRRK2 in vitro. PP1 activity on LRRK2 dephosphorylation was confirmed in cells using PP1 inhibition to reverse LRRK2 dephosphorylation induced by the potent LRRK2 kinase inhibitor LRRK2-IN1 as well as in R1441G mutant LRRK2. We also find that PP1 and LRRK2 can form a complex in cells. Furthermore, we observed that PP1 inhibition modulates LRRK2's cellular phenotype by reducing skein-like LRRK2-positive structures associated with dephosphorylation. In conclusion, our study reveals PP1 as the physiological LRRK2 phosphatase, responsible for LRRK2 dephosphorylation observed in PD mutant LRRK2 and after LRRK2 kinase inhibition.
ISSN: 0264-6021
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Biosignaling & Therapeutics
Research Group for Neurobiology and Gene Therapy
× corresponding author
# (joint) last author

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