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Hum Mol Genet. 2014 Sep 15;23(18):4887-905. doi: 10.1093/hmg/ddu202. Epub 2014 May 2.

A Parkinson's disease gene regulatory network identifies the signaling protein RGS2 as a modulator of LRRK2 activity and neuronal toxicity.

Author information

1
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.
2
Center for Individualized Medicine, Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
3
Department of Pharmacology and Experimental Therapeutics and.
4
Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital, Cambridge, MA 02139, USA.
5
Laboratory of Molecular Neurodegenerative Research, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
6
Reta Lila Weston Institute of Neurological Studies, UCL, Institute of Neurology, London, WC1N 1PJ, UK.
7
Neurodegenerative Studies Laboratory, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
8
Department of Neurology and Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
9
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.
10
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.

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.

PMID:
24794857
PMCID:
PMC4140468
DOI:
10.1093/hmg/ddu202
[Indexed for MEDLINE]
Free PMC Article

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