AUTHOR=Zhang Jinru , Li Kai , Wang Xiaobo , Smith Amber M. , Ning Bo , Liu Zhaohui , Liu Chunfeng , Ross Christopher A. , Smith Wanli W. TITLE=Curcumin Reduced H2O2- and G2385R-LRRK2-Induced Neurodegeneration JOURNAL=Frontiers in Aging Neuroscience VOLUME=13 YEAR=2021 URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2021.754956 DOI=10.3389/fnagi.2021.754956 ISSN=1663-4365 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.