LRRK2 kinase activity mediates toxic interactions between genetic mutation and oxidative stress in a Drosophila model: suppression by curcumin.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. The pathogenesis of PD is believed to involve both genetic susceptibility and environmental factors. Mutations in Leucine-rich repeat kinase 2 (LRRK2) cause genetic forms of PD, and the LRRK2 locus contributes to sporadic PD. Environmental toxins are believed to act in part by causing oxidative stress. Here we employed cell and Drosophila models to investigate the interaction between LRRK2 genetic mutations and oxidative stress. We found that H(2)O(2) increased LRRK2 kinase activity and enhanced LRRK2 cell toxicity in cultured cells and mouse primary cortical neurons. Furthermore, a sub-toxic dose of H(2)O(2) significantly shortened the survival of LRRK2 transgenic flies and augmented LRRK2-induced locomotor defects and dopamine neuron loss. Treatment with a LRRK2 kinase inhibitor (GW5074) or an anti-oxidant (curcumin) significantly suppressed these PD-like phenotypes in flies. Moreover, curcumin significantly reduced LRRK2 kinase activity and the levels of oxidized proteins, and thus acted as not only an antioxidant but also a LRRK2 kinase inhibitor. These results indicate that LRRK2 genetic alterations can interact with oxidative stress, converging on a pathogenic pathway that may be related to PD. These studies also identified curcumin as a LRRK2 kinase inhibitor that may be a useful candidate for LRRK2-linked PD intervention.
Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, PR China.
Dejun
D
Yang
Tianxia
T
Li
Zhaohui
Z
Liu
Nicolas
N
Arbez
Jianqun
J
Yan
Timothy H
TH
Moran
Christopher A
CA
Ross
Wanli W
WW
Smith
D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002540:Cerebral Cortex / Q000166:cytology; D003474:Curcumin / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047468:Immunoprecipitation; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D023421:Models, Animal; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D010636:Phenols / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis; D014162:Transfection
D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D007211:Indoles; D016877:Oxidants; D010636:Phenols; D049452:Green Fluorescent Proteins; D006861:Hydrogen Peroxide; C118135:OXSR1 protein, human; C543697:LRRK protein, Drosophila; D017346:Protein Serine-Threonine Kinases; D003474:Curcumin; C489251:5-iodo-3-((3,5-dibromo-4-hydroxyphenyl)methylene)-2-indolinone; D004298:Dopamine