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// Ching-Chi Chiu 1, 2, 3, * , Tu-Hsueh Yeh 1, 2, 4, 5, * , Chin-Song Lu 1, 2, 6, 7 , Yin-Cheng Huang 7, 8 , Yi-Chuan Cheng 9 , Ying-Zu Huang 1, 2, 6, 7, 10 , Yi-Hsin Weng 1, 2, 6, 7 , Yu-Chuan Liu 11 , Szu-Chia Lai 1, 2, 6, 7 , Ying-Ling Chen 3 , Yu-Jie Chen 1 , Chao-Lang Chen 1 , Hsin-Yi Chen 1, 6 , Yan-Wei Lin 1, 6 and Hung-Li Wang 1, 2, 6, 12 1 Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan 2 Healthy Aging Research Center, Chang Gung University College of Medicine, Taoyuan, Taiwan 3 Department of Nursing, Chang Gung University of Science and Technology, Taoyuan, Taiwan 4 Department of Neurology, Taipei Medical University Hospital, Taipei, Taiwan 5 School of Medicine, Taipei Medical University, Taipei, Taiwan 6 Division of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan 7 College of Medicine, Chang Gung University, Taoyuan, Taiwan 8 Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan 9 Graduate Institute of Biomedical Sciences, Chang Gung University College of Medicine, Taoyuan, Taiwan 10 Institute of Cognitive Neuroscience, National Central University, Taoyuan, Taiwan 11 Division of Sports Medicine, Taiwan Landseed Hospital, Taoyuan, Taiwan 12 Department of Physiology and Pharmacology, Chang Gung University College of Medicine, Taoyuan, Taiwan * These authors have contributed equally to this work Correspondence to: Hung-Li Wang, email: hlwns@mail.cgu.edu.tw Keywords: Parkinson’s disease, PARK14, PLA2G6, rotenone, mitochondrial dysfunction Received: March 01, 2017 Accepted: August 17, 2017 Published: September 15, 2017 ABSTRACT Mutations in the gene encoding Ca 2+ -independent phospholipase A 2 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.

Glioblastomas are among the most fatal brain tumors; however, the molecular determinants of their tumorigenic behavior are not adequately defined. In this study, we analyzed the role of KMT2A in the glioblastoma cell line U-87 MG. KMT2A knockdown promoted cell proliferation. Moreover, it increased the DNA methylation of NOTCH1 and NOTCH3 and reduced the expression of NOTCH1 and NOTCH3. NOTCH1 or NOTCH3 activation inhibited U-87 MG cell proliferation, whereas NOTCH1 and NOTCH3 inhibition by shRNAs induced cell proliferation, thus demonstrating the tumor-suppressive ability of NOTCH1 and NOTCH3 in U-87 MG cells. The induced cell proliferation caused by KMT2A knockdown could be nullified by using either constitutively active NOTCH1 or constitutively active NOTCH3. This result demonstrates that KMT2A positively regulates NOTCH1 and NOTCH3 and that this mechanism is essential for inhibiting the U-87 MG cell proliferation. The role of KMT2A knockdown in promoting tumor growth was further confirmed in vivo by transplanting U-87 MG cells into the brains of zebrafish larvae. In conclusion, we identified KMT2A-NOTCH as a negative regulatory cascade for glioblastoma cell proliferation, and this result provides important information for KMT2A- or NOTCH-targeted therapeutic strategies for brain tumors.