PARK14 PLA2G6 mutants are defective in preventing rotenone-induced mitochondrial dysfunction, ROS generation and activation of mitochondrial apoptotic pathway
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Ching-Chi Chiu1,2,3,*, Tu-Hsueh Yeh1,2,4,5,*, Chin-Song Lu1,2,6,7, Yin-Cheng Huang7,8, Yi-Chuan Cheng9, Ying-Zu Huang1,2,6,7,10, Yi-Hsin Weng1,2,6,7, Yu-Chuan Liu11, Szu-Chia Lai1,2,6,7, Ying-Ling Chen3, Yu-Jie Chen1, Chao-Lang Chen1, Hsin-Yi Chen1,6, Yan-Wei Lin1,6 and Hung-Li Wang1,2,6,12
1Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
2Healthy Aging Research Center, Chang Gung University College of Medicine, Taoyuan, Taiwan
3Department of Nursing, Chang Gung University of Science and Technology, Taoyuan, Taiwan
4Department of Neurology, Taipei Medical University Hospital, Taipei, Taiwan
5School of Medicine, Taipei Medical University, Taipei, Taiwan
6Division of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
7College of Medicine, Chang Gung University, Taoyuan, Taiwan
8Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
9Graduate Institute of Biomedical Sciences, Chang Gung University College of Medicine, Taoyuan, Taiwan
10Institute of Cognitive Neuroscience, National Central University, Taoyuan, Taiwan
11Division of Sports Medicine, Taiwan Landseed Hospital, Taoyuan, Taiwan
12Department of Physiology and Pharmacology, Chang Gung University College of Medicine, Taoyuan, Taiwan
*These authors have contributed equally to this work
Hung-Li Wang, email: firstname.lastname@example.org
Keywords: Parkinson’s disease, PARK14, PLA2G6, rotenone, mitochondrial dysfunction
Received: March 01, 2017 Accepted: August 17, 2017 Published: September 15, 2017
Mutations in the gene encoding Ca2+-independent phospholipase A2 group 6 (PLA2G6) cause the recessive familial type 14 of Parkinson’s disease (PARK14). Mitochondrial dysfunction is involved in the pathogenesis of Parkinson’s disease (PD). PLA2G6 is believed to be required for maintaining mitochondrial function. In the present study, rotenone-induced cellular model of PD was used to investigate possible molecular pathogenic mechanism of PARK14 mutant PLA2G6-induced PD. Overexpression of wild-type (WT) PLA2G6 ameliorated rotenone-induced apoptotic death of SH-SY5Y dopaminergic cells. PARK14 mutant (D331Y), (G517C), (T572I), (R632W), (N659S) or (R741Q) PLA2G6 failed to prevent rotenone-induced activation of mitochondrial apoptotic pathway and exert a neuroprotective effect. WT PLA2G6, but not PARK14 mutant PLA2G6, prevented rotenone-induced mitophagy impairment. In contrast to WT PLA2G6, PARK14 mutant PLA2G6 was ineffective in attenuating rotenone-induced decrease in mitochondrial membrane potential and increase in the level of mitochondrial superoxide. WT PLA2G6, but not PARK14 PLA2G6 mutants, restored enzyme activity of mitochondrial complex I and cellular ATP content in rotenone-treated SH-SY5Y dopaminergic cells. In contrast to WT PLA2G6, PARK14 mutant PLA2G6 failed to prevent rotenone-induced mitochondrial lipid peroxidation and cytochrome c release. These results suggest that PARK14 PLA2G6 mutants lose their ability to maintain mitochondrial function and are defective inpreventing mitochondrial dysfunction, ROS production and activation of mitochondrial apoptotic pathway in rotenone-induced cellular model of PD.
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