LRRK2 kinase activity mediates toxic interactions between genetic mutation and oxidative stress in a Drosophila model: Suppression by curcumin

Neurobiology of Disease

Wanli W. Smith¹  Tianxia Li²  Timothy H. Moran³  Zhaohui Liu⁴  Nicolas Arbez⁴  Dejun Yang⁵  Christopher A. Ross⁵  Jianqun Yan⁶ 

[1] Correspondence to: J. Yan, Department of Physiology and Pathophysiology, Xi’an Jiaotong University School of Medicine, Xi’an, Shaanxi 710061, PR China.;Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA;Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA;Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA;Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, PR China;Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA;

关键词: LRRK2;    H2O2;    Parkinson's disease;    Drosophila;    Dopamine neuron;    Curcumin;   

DOI  :  

来源: DOAJ

【 摘 要 】

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 H2O2 increased LRRK2 kinase activity and enhanced LRRK2 cell toxicity in cultured cells and mouse primary cortical neurons. Furthermore, a sub-toxic dose of H2O2 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.

【 授权许可】

Unknown