Leucine-rich repeat kinase 2 interacts with p21-activated kinase 6 to control neurite complexity in mammalian brain

摘要: Leucine-rich repeat kinase 2 (LRRK2) is a causative gene for Parkinson's disease, but the physiological function and mechanism(s) by which cellular activity of LRRK2 regulated are poorly understood. Here, we identified p21-activated 6 (PAK6) as novel interactor GTPase/ROC domain LRRK2. kinases serine-threonine that serve targets small GTP binding proteins Cdc42 Rac1 have been implicated in different morphogenetic processes through remodeling actin cytoskeleton such synapse formation neuritogenesis. Using an in vivo neuromorphology assay, show PAK6 positive regulator neurite outgrowth required this function. Analyses post-mortem brain tissue from idiopathic G2019S carriers reveal increase activation state, whereas knock-out mice display reduced phosphorylation substrates. Taken together, these results support critical role GTPase cytoskeletal dynamics PAK6, provide valuable platform to unravel mechanism underlying LRRK2-mediated pathophysiology. We propose leucine-rich (LRRK2), involved disease (PD). In health, regulates complexity its function, (a) aberrantly activated LRRK2-linked PD (b) suggesting toxicity mediated PAK6.