PARK14 (D331Y) PLA2G6 Causes Early-Onset Degeneration of Substantia Nigra Dopaminergic Neurons by Inducing Mitochondrial Dysfunction, ER Stress, Mitophagy Impairment and Transcriptional Dysregulation in a Knockin Mouse Model

被引：0
作者：
Ching-Chi Chiu
Chin-Song Lu
Yi-Hsin Weng
Ying-Ling Chen
Ying-Zu Huang
Rou-Shayn Chen
Yi-Chuan Cheng
Yin-Cheng Huang
Yu-Chuan Liu
Szu-Chia Lai
Kun-Jun Lin
Yan-Wei Lin
Yu-Jie Chen
Chao-Lang Chen
Tu-Hsueh Yeh
Hung-Li Wang
机构：
[1] Chang Gung Memorial Hospital at Linkou,Neuroscience Research Center
[2] Chang Gung University of Science and Technology,Department of Nursing
[3] Chang Gung University College of Medicine,Healthy Aging Research Center
[4] Chang Gung Memorial Hospital at Linkou,Division of Movement Disorders, Department of Neurology
[5] Chang Gung University,College of Medicine
[6] National Central University,Institute of Cognitive Neuroscience
[7] Chang Gung University College of Medicine,Graduate Institute of Biomedical Sciences
[8] Chang Gung Memorial Hospital at Linkou,Department of Neurosurgery
[9] Taiwan Landseed Hospital,Division of Sports Medicine
[10] Chang Gung Memorial Hospital at Linkou,Molecular Imaging Center
[11] Taipei Medical University Hospital,Department of Neurology
[12] Taipei Medical University,School of Medicine
[13] Chang Gung University College of Medicine,Department of Physiology and Pharmacology
来源：
Molecular Neurobiology | 2019年 / 56卷
关键词：
Parkinson’s disease; PARK14; (D331Y) PLA2G6; Knockin mice;
D O I：
暂无
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学科分类号：
摘要：
PARK14 patients with homozygous (D331Y) PLA2G6 mutation display motor deficits of pure early-onset Parkinson’s disease (PD). The aim of this study is to investigate the pathogenic mechanism of mutant (D331Y) PLA2G6-induced PD. We generated knockin (KI) mouse model of PARK14 harboring homozygous (D331Y) PLA2G6 mutation. Then, we investigated neuropathological and neurological phenotypes of PLA2G6D331Y/D331Y KI mice and molecular pathogenic mechanisms of (D331Y) PLA2G6-induced degeneration of substantia nigra (SN) dopaminergic neurons. Six-or nine-month-old PLA2G6D331Y/D331Y KI mice displayed early-onset cell death of SNpc dopaminergic neurons. Lewy body pathology was found in the SN of PLA2G6D331Y/D331Y mice. Six-or nine-month-old PLA2G6D331Y/D331Y KI mice exhibited early-onset parkinsonism phenotypes. Disrupted cristae of mitochondria were found in SNpc dopaminergic neurons of PLA2G6D331Y/D331Y mice. PLA2G6D331Y/D331Y mice displayed mitochondrial dysfunction and upregulated ROS production, which may lead to activation of apoptotic cascade. Upregulated protein levels of Grp78, IRE1, PERK, and CHOP, which are involved in activation of ER stress, were found in the SN of PLA2G6D331Y/D331Y mice. Protein expression of mitophagic proteins, including parkin and BNIP3, was downregulated in the SN of PLA2G6D331Y/D331Y mice, suggesting that (D331Y) PLA2G6 mutation causes mitophagy dysfunction. In the SN of PLA2G6D331Y/D331Y mice, mRNA levels of eight genes that are involved in neuroprotection/neurogenesis were decreased, while mRNA levels of two genes that promote apoptotic death were increased. Our results suggest that PARK14 (D331Y) PLA2G6 mutation causes degeneration of SNpc dopaminergic neurons by causing mitochondrial dysfunction, elevated ER stress, mitophagy impairment, and transcriptional abnormality.
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页码：3835 / 3853
页数：18
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