title: A Parkinson's disease gene regulatory network identifies the signaling protein RGS2 as a modulator of LRRK2 activity and neuronal toxicity.
abstract: Mutations in LRRK2 are one of the primary genetic causes of Parkinson's disease (PD). LRRK2 contains a kinase and a GTPase domain, and familial PD mutations affect both enzymatic activities. However, the signaling mechanisms regulating LRRK2 and the pathogenic effects of familial mutations remain unknown. Identifying the signaling proteins that regulate LRRK2 function and toxicity remains a critical goal for the development of effective therapeutic strategies. In this study, we apply systems biology tools to human PD brain and blood transcriptomes to reverse-engineer a LRRK2-centered gene regulatory network. This network identifies several putative master regulators of LRRK2 function. In particular, the signaling gene RGS2, which encodes for a GTPase-activating protein (GAP), is a key regulatory hub connecting the familial PD-associated genes DJ-1 and PINK1 with LRRK2 in the network. RGS2 expression levels are reduced in the striata of LRRK2 and sporadic PD patients. We identify RGS2 as a novel interacting partner of LRRK2 in vivo. RGS2 regulates both the GTPase and kinase activities of LRRK2. We show in mammalian neurons that RGS2 regulates LRRK2 function in the control of neuronal process length. RGS2 is also protective against neuronal toxicity of the most prevalent mutation in LRRK2, G2019S. We find that RGS2 regulates LRRK2 function and neuronal toxicity through its effects on kinase activity and independently of GTPase activity, which reveals a novel mode of action for GAP proteins. This work identifies RGS2 as a promising target for interfering with neurodegeneration due to LRRK2 mutations in PD patients.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics and Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02215, USA, Howard Hughes Medical Institute, Department of Biomedical Engineering and Center of Synthetic Biology, Boston University, Boston, MA 02215, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Dusonchet
authors.affiliation: Center for Individualized Medicine, Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Hu
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Experimental Therapeutics and.
authors.forename: Maria
authors.initials: M
authors.lastname: Guillily
authors.affiliation: Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital, Cambridge, MA 02139, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Laboratory of Molecular Neurodegenerative Research, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Klodjan
authors.initials: K
authors.lastname: Stafa
authors.affiliation: Department of Pharmacology and Experimental Therapeutics and.
authors.forename: Claudio
authors.initials: C
authors.lastname: Derada Troletti
authors.affiliation: Department of Pharmacology and Experimental Therapeutics and.
authors.forename: Joon Y
authors.initials: JY
authors.lastname: Boon
authors.affiliation: Department of Pharmacology and Experimental Therapeutics and.
authors.forename: Shamol
authors.initials: S
authors.lastname: Saha
authors.affiliation: Laboratory of Molecular Neurodegenerative Research, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Liliane
authors.initials: L
authors.lastname: Glauser
authors.affiliation: Reta Lila Weston Institute of Neurological Studies, UCL, Institute of Neurology, London, WC1N 1PJ, UK.
authors.forename: Adamantios
authors.initials: A
authors.lastname: Mamais
authors.affiliation: Department of Pharmacology and Experimental Therapeutics and.
authors.forename: Allison
authors.initials: A
authors.lastname: Citro
authors.affiliation: Department of Pharmacology and Experimental Therapeutics and.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Youmans
authors.affiliation: Department of Pharmacology and Experimental Therapeutics and.
authors.forename: LiQun
authors.initials: L
authors.lastname: Liu
authors.affiliation: Neurodegenerative Studies Laboratory, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Schneider
authors.affiliation: Neurodegenerative Studies Laboratory, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Aebischer
authors.affiliation: Department of Neurology and Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yue
authors.affiliation: Reta Lila Weston Institute of Neurological Studies, UCL, Institute of Neurology, London, WC1N 1PJ, UK.
authors.forename: Rina
authors.initials: R
authors.lastname: Bandopadhyay
authors.affiliation: Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital, Cambridge, MA 02139, USA.
authors.forename: Marcie A
authors.initials: MA
authors.lastname: Glicksman
authors.affiliation: Laboratory of Molecular Neurodegenerative Research, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Moore
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02215, USA, Howard Hughes Medical Institute, Department of Biomedical Engineering and Center of Synthetic Biology, Boston University, Boston, MA 02215, USA, bwolozin@bu.edu jcollins@bu.edu.
authors.forename: James J
authors.initials: JJ
authors.lastname: Collins
authors.affiliation: Department of Pharmacology and Experimental Therapeutics and Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, USA, bwolozin@bu.edu jcollins@bu.edu.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wolozin
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000378:metabolism; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D015513:Oncogene Proteins / Q000378:metabolism; D010300:Parkinson Disease / Q000097:blood / Q000235:genetics* / Q000473:pathology*; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020710:RGS Proteins / Q000378:metabolism*; D049490:Systems Biology / Q000379:methods; D059467:Transcriptome; D000099202:PTEN-Induced Putative Kinase
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D015513:Oncogene Proteins; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D020710:RGS Proteins; D000099202:PTEN-Induced Putative Kinase; C087182:RGS2 protein, human; C495280:LRRK2 protein, human; C105131:PARK7 protein, human