title: Fbxl18 targets LRRK2 for proteasomal degradation and attenuates cell toxicity.
abstract: Dominantly inherited mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common causes of familial Parkinson's disease (PD) and LRRK2 polymorphisms are associated with increased risk for idiopathic PD. However, the molecular mechanisms by which these mutations cause PD remain uncertain. In vitro studies indicate that disease-linked mutations in LRRK2 increase LRRK2 kinase activity and LRRK2-mediated cell toxicity. Identifying LRRK2-interacting proteins and determining their effects on LRRK2 are important for understanding LRRK2 function and for delineating the pathophysiological mechanisms of LRRK2 mutations. Here we identified a novel protein, F-box and leucine-rich repeat domain-containing protein 18 (Fbxl18) that physically associates with LRRK2. We demonstrated that Fbxl18 is a component of a Skp1-Cullin1-F-box ubiquitin ligase complex that regulates the abundance of LRRK2 by selectively targeting phosphorylated LRRK2 for ubiquitination and proteasomal degradation. Knockdown of endogenous Fbxl18 stabilized LRRK2 abundance while protein kinase C activation enhanced LRRK2 degradation by Fbxl18. Dephosphorylation of LRRK2 blocked Fbxl18 association with LRRK2. Taken together, we have identified potential mechanisms for LRRK2 regulation by kinase signaling pathways. Furthermore, Fbxl18 prevented caspase activation and cell death caused by LRRK2 and PD-linked mutant LRRK2. This reveals novel targets for developing potential therapies for familial and idiopathic PD.
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Ding
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Barodia
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Lisha
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA; Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: mattgoldberg@uab.edu.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Goldberg
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D016923:Cell Death / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D002522:Chlorocebus aethiops; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D009474:Neurons / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*
chemical_list: D044783:F-Box Proteins; C000601116:FBXL18 protein, human; C489149:FBXO7 protein, human; C000626370:Fbxl18 protein, mouse; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D046988:Proteasome Endopeptidase Complex
keywords: Cell death; Kinase; LRRK2