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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.

SUBMITTER: Dusonchet J

PROVIDER: S-EPMC4140468 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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

Dusonchet Julien J Li Hu H Guillily Maria M Liu Min M Stafa Klodjan K Derada Troletti Claudio C Boon Joon Y JY Saha Shamol S Glauser Liliane L Mamais Adamantios A Citro Allison A Youmans Katherine L KL Liu LiQun L Schneider Bernard L BL Aebischer Patrick P Yue Zhenyu Z Bandopadhyay Rina R Glicksman Marcie A MA Moore Darren J DJ Collins James J JJ Wolozin Benjamin B

Human molecular genetics 20140502 18

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 bio ...[more]

PMID: 24794857

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Project description:Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of autosomal dominant familial Parkinson's disease (PD) and also contribute to idiopathic PD. LRRK2 encodes a large multi-domain protein with GTPase and kinase activity. Initial data indicates that an intact functional GTPase domain is critically required for LRRK2 kinase activity. PD-associated mutations in LRRK2, including the most common G2019S variant, have variable effects on enzymatic activity but commonly alter neuronal process morphology. The mechanisms underlying the intrinsic and extrinsic regulation of LRRK2 GTPase and kinase activity, and the pathogenic effects of familial mutations, are incompletely understood. Here, we identify a novel functional interaction between LRRK2 and ADP-ribosylation factor GTPase-activating protein 1 (ArfGAP1). LRRK2 and ArfGAP1 interact in vitro in mammalian cells and in vivo in brain, and co-localize in the cytoplasm and at Golgi membranes. PD-associated and functional mutations that alter the GTPase activity of LRRK2 modulate the interaction with ArfGAP1. The GTP hydrolysis activity of LRRK2 is markedly enhanced by ArfGAP1 supporting a role for ArfGAP1 as a GTPase-activating protein for LRRK2. Unexpectedly, ArfGAP1 promotes the kinase activity of LRRK2 suggesting a potential role for GTP hydrolysis in kinase activation. Furthermore, LRRK2 robustly and directly phosphorylates ArfGAP1 in vitro. Silencing of ArfGAP1 expression in primary cortical neurons rescues the neurite shortening phenotype induced by G2019S LRRK2 overexpression, whereas the co-expression of ArfGAP1 and LRRK2 synergistically promotes neurite shortening in a manner dependent upon LRRK2 GTPase activity. Neurite shortening induced by ArfGAP1 overexpression is also attenuated by silencing of LRRK2. Our data reveal a novel role for ArfGAP1 in regulating the GTPase activity and neuronal toxicity of LRRK2; reciprocally, LRRK2 phosphorylates ArfGAP1 and is required for ArfGAP1 neuronal toxicity. ArfGAP1 may represent a promising target for interfering with LRRK2-dependent neurodegeneration in familial and sporadic PD.

Project description:Estrogens control multiple functions of hormone-responsive breast cancer cells. They regulate diverse physiological processes in various tissues through genomic and non-genomic mechanisms that result in activation or repression of gene expression. Transcription regulation upon estrogen stimulation is a critical biological process underlying the onset and progress of the majority of breast cancer. ER? requires distinct co-regulator or modulators for efficient transcriptional regulation, and they form a regulatory network. Knowing this regulatory network will enable systematic study of the effect of ER? on breast cancer.To investigate the regulatory network of ER? and discover novel modulators of ER? functions, we proposed an analytical method based on a linear regression model to identify translational modulators and their network relationships. In the network analysis, a group of specific modulator and target genes were selected according to the functionality of modulator and the ER? binding. Network formed from targets genes with ER? binding was called ER? genomic regulatory network; while network formed from targets genes without ER? binding was called ER? non-genomic regulatory network. Considering the active or repressive function of ER?, active or repressive function of a modulator, and agonist or antagonist effect of a modulator on ER?, the ER?/modulator/target relationships were categorized into 27 classes.Using the gene expression data and ER? Chip-seq data from the MCF-7 cell line, the ER? genomic/non-genomic regulatory networks were built by merging ER?/ modulator/target triplets (TF, M, T), where TF refers to the ER?, M refers to the modulator, and T refers to the target. Comparing these two networks, ER? non-genomic network has lower FDR than the genomic network. In order to validate these two networks, the same network analysis was performed in the gene expression data from the ZR-75.1 cell. The network overlap analysis between two cancer cells showed 1% overlap for the ER? genomic regulatory network, but 4% overlap for the non-genomic regulatory network.We proposed a novel approach to infer the ER?/modulator/target relationships, and construct the genomic/non-genomic regulatory networks in two cancer cells. We found that the non-genomic regulatory network is more reliable than the genomic regulatory network.

Dataset Information

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

Publications

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

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