title: Leucine-rich repeat kinase 2 interacts with p21-activated kinase 6 to control neurite complexity in mammalian brain.
abstract: Leucine-rich repeat kinase 2 (LRRK2) is a causative gene for Parkinson's disease, but the physiological function and the mechanism(s) by which the cellular activity of LRRK2 is regulated are poorly understood. Here, we identified p21-activated kinase 6 (PAK6) as a novel interactor of the GTPase/ROC domain of LRRK2. 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 PAK6 is a positive regulator of neurite outgrowth and that LRRK2 is required for this function. Analyses of post-mortem brain tissue from idiopathic and LRRK2 G2019S carriers reveal an increase in PAK6 activation state, whereas knock-out LRRK2 mice display reduced PAK6 activation and phosphorylation of PAK6 substrates. Taken together, these results support a critical role of LRRK2 GTPase domain in cytoskeletal dynamics in vivo through the novel interactor PAK6, and provide a valuable platform to unravel the mechanism underlying LRRK2-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.
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Civiero
authors.affiliation: San Raffaele Science Park and Università Vita-Salute San Raffaele, Milano, Italy.
authors.forename: Maria Daniela
authors.initials: MD
authors.lastname: Cirnaru
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging/NIH, Bethesda, Maryland, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Beilina
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.|Laboratory for Neurobiology and Gene Therapy, KU Leuven, Leuven, Belgium.
authors.forename: Umberto
authors.initials: U
authors.lastname: Rodella
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Russo
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Belluzzi
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, KU Leuven, Leuven, Belgium.
authors.forename: Evy
authors.initials: E
authors.lastname: Lobbestael
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, KU Leuven, Leuven, Belgium.
authors.forename: Lauran
authors.initials: L
authors.lastname: Reyniers
authors.affiliation: Department of Molecular Neuroscience UCL, Reta Lila Weston Institute of Neurological Studies, Institute of Neurology, London, UK.
authors.forename: Geshanthi
authors.initials: G
authors.lastname: Hondhamuni
authors.affiliation: School of Pharmacy, University of Reading, Reading, UK.|Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Lewis
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, KU Leuven, Leuven, Belgium.|Leuven Viral Vector Core, KU Leuven, Leuven, Belgium.
authors.forename: Chris
authors.initials: C
authors.lastname: Van den Haute
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, KU Leuven, Leuven, Belgium.
authors.forename: Veerle
authors.initials: V
authors.lastname: Baekelandt
authors.affiliation: Department of Molecular Neuroscience UCL, Reta Lila Weston Institute of Neurological Studies, Institute of Neurology, London, UK.
authors.forename: Rina
authors.initials: R
authors.lastname: Bandopadhyay
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Bubacco
authors.affiliation: San Raffaele Science Park and Università Vita-Salute San Raffaele, Milano, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Piccoli
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging/NIH, Bethesda, Maryland, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cookson
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, KU Leuven, Leuven, Belgium.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Taymans
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Greggio
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D006801:Humans; D007930:Leucine / Q000235:genetics*; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008322:Mammals / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D016501:Neurites / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D054462:p21-Activated Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; C429007:PAK6 protein, human; C532966:Pak6 protein, mouse; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D007930:Leucine
keywords: LRRK2; Parkinson's disease; neurodegeneration; neuronal cyto-skeleton; p21-activated kinases