Abstract
Mutations in leucine-rich repeat kinase 2 gene (LRRK2) are the most frequent genetic factors contributing to Parkinson's disease (PD). G2385R-LRRK2 increases the risk for PD susceptibility in the Chinese population. However, the pathological role of G2385R-LRRK2 is not clear. In this study, we investigate the roles of G2385R-LRRK2 in neurodegeneration underlying PD pathogenesis using cell biology and pharmacology approaches. We demonstrated that expression of G2385R-LRRK2-induced neurotoxicity in human neuroblastoma SH-SY5Y and mouse primary neurons. G2385R-LRRK2 increased mitochondrial ROS, activates caspase-3/7, and increased PARP cleavage, resulting in neurotoxicity. Treatment with curcumin (an antioxidant) significantly protected against G2385R-LRRK2-induced neurodegeneration by reducing mitochondrial ROS, caspase-3/7 activation, and PARP cleavage. We also found that the cellular environmental stressor, H2O2 significantly promotes both WT-LRRK2- and G2385R-LRRK2-induced neurotoxicity by increasing mitochondrial ROS, caspase-3/7 activation, and PARP cleavage, while curcumin attenuated this combined neurotoxicity. These findings not only provide a novel understanding of G2385R roles in neurodegeneration and environment interaction but also provide a pharmacological approach for intervention for G2385R-LRRK2-linked PD.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disease with movement disorders
We found that transient expression of G2385R-leucine-rich repeat kinase 2 gene (LRRK2) significantly induced neurotoxicity in human neuroblastoma SH-SY5Y cells compared with vector cells alone or cells expressing wild-type (WT)-LRRK2 (Figure 1)
While curcumin treatment significantly attenuated PARP cleavageinduced by H2O2 and G2385R-LRRK2 compared with vehicle controls (Figure 6)
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disease with movement disorders. According to the Human Gene Mutation Database, more than 100 LRRK2 variants have been reported to be associated with PD (http://www.hgmd.cf.ac.uk/ac/index.php). Most PD-linked LRRK2 mutations (e.g., G2019S) create an increase in kinase and GTPase activities, which play critical roles in PD pathogenesis (Liu et al, 2011a). We found that overexpression of G2385RLRRK2 induced neurotoxicity via an increase in oxidative stress, thereby activating the apoptotic pathway, and that curcumin (an antioxidant) significantly protected against G2385R-LRRK2-induced neurotoxicity. These findings provide novel insight into the mechanisms of G2385R-LRRK2-linked neurodegeneration and a potential treatment strategy for PD patients harboring G2385R.
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