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Leucine‐rich repeat kinase 2 interacts with p21‐activated kinase 6 to control neurite complexity in mammalian brain
Author(s) -
Civiero Laura,
Cirnaru Maria Daniela,
Beilina Alexandra,
Rodella Umberto,
Russo Isabella,
Belluzzi Elisa,
Lobbestael Evy,
Reyniers Lauran,
Hondhamuni Geshanthi,
Lewis Patrick A.,
Van den Haute Chris,
Baekelandt Veerle,
Bandopadhyay Rina,
Bubacco Luigi,
Piccoli Giovanni,
Cookson Mark R.,
Taymans JeanMarc,
Greggio Elisa
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13369
Subject(s) - lrrk2 , microbiology and biotechnology , kinase , neurite , biology , rac1 , gtpase , protein kinase domain , phosphorylation , map kinase kinase kinase , pak1 , ask1 , actin cytoskeleton , cyclin dependent kinase 9 , map2k7 , cyclin dependent kinase 2 , signal transduction , protein kinase a , cytoskeleton , biochemistry , in vitro , gene , mutant , cell , mutation
Leucine‐rich repeat kinase 2 ( LRRK 2 ) is a causative gene for Parkinson's disease, but the physiological function and the mechanism(s) by which the cellular activity of LRRK 2 is regulated are poorly understood. Here, we identified p21‐activated kinase 6 ( PAK 6) as a novel interactor of the GTPase/ ROC domain of LRRK 2. p21‐activated kinases are serine‐threonine kinases that serve as targets for the small GTP binding proteins Cdc42 and Rac1 and have been implicated in different morphogenetic processes through remodeling of the actin cytoskeleton such as synapse formation and neuritogenesis. Using an in vivo neuromorphology assay, we show that PAK 6 is a positive regulator of neurite outgrowth and that LRRK 2 is required for this function. Analyses of post‐mortem brain tissue from idiopathic and LRRK 2 G2019S carriers reveal an increase in PAK 6 activation state, whereas knock‐out LRRK 2 mice display reduced PAK 6 activation and phosphorylation of PAK 6 substrates. Taken together, these results support a critical role of LRRK 2 GTPase domain in cytoskeletal dynamics in vivo through the novel interactor PAK 6, and provide a valuable platform to unravel the mechanism underlying LRRK 2‐mediated pathophysiology.We propose p21‐activated kinase 6 (PAK6) as a novel interactor of leucine‐rich repeat kinase 2 (LRRK2), a kinase involved in Parkinson's disease (PD). In health, PAK6 regulates neurite complexity in the brain and LRRK2 is required for its function, (a) whereas PAK6 is aberrantly activated in LRRK2‐linked PD brain (b) suggesting that LRRK2 toxicity is mediated by PAK6.