A Parkinson's disease gene regulatory network identifies the signaling protein RGS2 as a modulator of LRRK2 activity and neuronal toxicity
Year: 2014
Type: article
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.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddu202
Authors: Julien Dusonchet, Hu Li, Maria Guillily, Min Liu, Klodjan Stafa, Claudio Derada Troletti, Joon Y. Boon, Shamol Saha, Liliane Glauser, Adamantios Mamais, Allison Citro, Katherine L. Youmans, LiQun Liu, Bernard L. Schneider, Patrick Aebischer, Zhenyu Yue, Rina Bandopadhyay, Marcie A. Glicksman, Darren J. Moore, James J. Collins, Benjamin Wolozin
Institutions: Boston University, Howard Hughes Medical Institute, Harvard University, Wyss Institute for Biologically Inspired Engineering, Mayo Clinic, Brigham and Women's Hospital, Harvard NeuroDiscovery Center, École Polytechnique Fédérale de Lausanne, UCL Queen Square Institute of Neurology, University College London, Icahn School of Medicine at Mount Sinai
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: National Science Foundation, Howard Hughes Medical Institute, Mayo Clinic, Harvard NeuroDiscovery Center, Emory University, Les Laboratories Pierre Fabre, École Polytechnique Fédérale de Lausanne, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, National Institutes of Health, National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences
Awards: LRRK2 and RhoGTPases: Local translation in neurodegeneration, Molecular Mechanism of LRRK2 Biology and Pathology in Parkinson's Disease, G3933327778, Small Molecule Probes for Elucidating LRRK2 Kinase Functions, LRRK2 Cell Biology and Parkinson's Disease, G6271991303, LRRK2 and Neurodegeneration, Boston University Alzheimer's Disease Center, Ubiquitination/Receptor Signaling--Regulation by Parkin, Interaction Between Genes and the Mitochondria in Parkin, Neuronal Autophagy: a Cell-Autonomous Protection Mechanism
OpenAlex ID: W2107901782