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.
Highlights
ROCO proteins constitute a family of proteins with a Raslike domain, termed ras of complex (ROC), which is always followed by a C-terminus Of ROC (COR) domain of unclear function (Bosgraaf and Van Haastert 2003)
We found that p21-activated kinase 6 (PAK6) is hyperactivated in G2019S and idiopathic Parkinson’s disease (PD) post-mortem brains compared to healthy controls, highlighting PAK6 as a novel pharmacological target in PD
leucine-rich repeat kinase 2 (LRRK2) interacts with PAK6 In a previous study, we reported high confidence interactors of LRRK2 identified by probing protoarrays with fulllength recombinant LRRK2 protein (Beilina et al 2014; Reyniers et al 2014)
Summary
ROCO proteins constitute a family of proteins with a Raslike domain, termed ras of complex (ROC), which is always followed by a C-terminus Of ROC (COR) domain of unclear function (Bosgraaf and Van Haastert 2003). LRRK2 has been linked with several pathways relevant for neuronal physiology, including autophagy (Plowey et al 2008; Gomez-Suaga et al 2012; Manzoni et al 2013), vesicle trafficking (Piccoli et al 2011; MacLeod et al 2013; Cirnaru et al 2014), neurite outgrowth (MacLeod et al 2006; Dachsel et al 2010; Winner et al 2011), cytoskeletal dynamics (Kett et al 2011; Caesar et al 2013, 2015; Habig et al 2013; Law et al 2013), and inflammation (reviewed in Russo et al 2014) Some of these functions may appear unrelated, they all rely on the presence of a functional cytoskeleton. We found that PAK6 is hyperactivated in G2019S and idiopathic PD (iPD) post-mortem brains compared to healthy controls, highlighting PAK6 as a novel pharmacological target in PD
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