Document Detail


LRRK2 enhances oxidative stress-induced neurotoxicity via its kinase activity.
MedLine Citation:
PMID:  19769964     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
LRRK2 is an autosomal dominant gene whose mutations cause familial Parkinson's disease (PD). The LRRK2 protein contains a functional kinase and a GTPase domain. PD phenotypes caused by LRRK2 mutations are similar to those of idiopathic PD, implying that LRRK2 is an important participant in PD pathogenesis. Of LRRK2's PD-specific mutations, the G2019S is the most frequently observed one. Its over-expression is known to increase kinase activity and neurotoxicity compared to wild type (WT) LRRK2. Here, using a simple colorimetric cell viability assay, we analyzed LRRK2's neurotoxicity in dopaminergic SN4741 cells following treatment with hydrogen peroxide. When WT, G2019S, or empty vector was expressed in SN4741 cells, cell death was modestly and significantly increased in the order of G2019S>WT>vector. When these transfected cells were treated with hydrogen peroxide to mimic oxidative stress, cellular neurotoxicity was enhanced in the same order (i.e. G2019S>WT>vector). Moreover, incubation of SN4741 cells with conditioned medium from cells expressing G2019S and subjected to hydrogen peroxide treatment exhibited 10-15% more cell death than conditioned medium from cells transfected with vector or WT, suggesting that G2019S-expressing cells secrete a factor(s) affecting viability of neighboring cells. The kinase domain was mapped to be responsible for oxidative stress-induced neurotoxicity. In addition, over-expression of WT and G2019S LRRK2 lead to a weak, but significant, increase in intracellular reactive oxygen species (ROS) in the order of G2019S>WT as measured by DCFH-DA assay in both the presence and absence of H(2)O(2) treatment. Furthermore, in G2019S-expressing cells, co-expression of the anti-oxidant protein DJ-1 or ERK inhibitor treatment restored survival rate to a level similar to that of cells transfected with control vector under H(2)O(2) treatment. Taken together, our data suggest that the LRRK2 kinase domain increases the generation of ROS and causes enhanced neurotoxicity under H(2)O(2) treatment, which can be at least partially rescued by DJ-1 or the ERK inhibitor.
Authors:
Hye Young Heo; Ji-Min Park; Cy-Hyun Kim; Baek Soo Han; Kwang-Soo Kim; Wongi Seol
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-09-19
Journal Detail:
Title:  Experimental cell research     Volume:  316     ISSN:  1090-2422     ISO Abbreviation:  Exp. Cell Res.     Publication Date:  2010 Feb 
Date Detail:
Created Date:  2010-02-01     Completed Date:  2010-03-02     Revised Date:  2012-06-25    
Medline Journal Info:
Nlm Unique ID:  0373226     Medline TA:  Exp Cell Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  649-56     Citation Subset:  IM    
Copyright Information:
Copyright 2009 Elsevier Inc. All rights reserved.
Affiliation:
Institute for Brain Science and Technology, Busan, South Korea.
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MeSH Terms
Descriptor/Qualifier:
Biological Assay / methods
Blotting, Western
Cell Survival
Cells, Cultured
Cloning, Molecular
Enzyme Inhibitors / pharmacology
Genetic Vectors
Humans
Hydrogen Peroxide / pharmacology
Intracellular Signaling Peptides and Proteins / pharmacology
Mutation / genetics
Neurons / pathology*
Oncogene Proteins / pharmacology
Oxidative Stress / drug effects,  genetics*
Phosphotransferases / metabolism*
Plasmids
Protein-Serine-Threonine Kinases / genetics,  metabolism*
Reactive Oxygen Species / analysis
Signal Transduction
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Intracellular Signaling Peptides and Proteins; 0/Oncogene Proteins; 0/PARK7 protein, human; 0/Reactive Oxygen Species; 7722-84-1/Hydrogen Peroxide; EC 2.7.-/Phosphotransferases; EC 2.7.11.1/LRRK2 protein, human; EC 2.7.11.1/Protein-Serine-Threonine Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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