title: Loss of PINK1 inhibits apoptosis by upregulating α-synuclein in inflammation-sensitized hypoxic-ischemic injury in the immature brains.
abstract: The incidence of preterm birth is rising worldwide. Among preterm infants, many face a lifetime of neurologic impairments. Recent studies have revealed that systemic inflammation can sensitize the immature brain to hypoxic-ischemic (HI) injury. Therefore, it is important to identify the mechanisms involved in inflammation-sensitized HI injury in immature brains. PTEN-induced putative kinase 1 (PINK1) is a regulatory protein that is highly expressed in the brain. We have previously found that PINK1 gene knockout can protect matured brains from HI injury in postnatal day 10 mice. However, the mechanisms are unknown. In this study, we employed an inflammation-sensitized HI injury model using postnatal day 3 mice to study the roles and mechanisms that PINK1 plays in the immature brains. Lipopolysaccharide (LPS) was injected intraperitoneally into the mice before HI treatment to set up the model. We found that PINK1-knockout mice had fewer brain infarcts and less cell apoptosis than did the wild-type mice. Furthermore, we found that α-synuclein was markedly higher in the PINK1-knockout mice than in the wild-type mice, and inhibition of α-synuclein through small interfering RNA (siRNA) reversed the protective effect in the PINK1-knockout mice. Collectively, these findings indicate that loss of PINK1 plays a novel role in the protection of inflammation-sensitized HI brain damage.
authors.affiliation: Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China; Department of Pediatrics, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou 325027, China. Electronic address: zhujianghu2005@163.com.
authors.forename: Jianghu
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China. Electronic address: quyi712002@163.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Department of Pediatrics, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou 325027, China. Electronic address: linzhenlang@hotmail.com.
authors.forename: Zhenlang
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China. Electronic address: hanyue80@163.com.
authors.forename: Fengyan
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China. Electronic address: zhanglihk@126.com.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China. Electronic address: 1027996742@qq.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China. Electronic address: cjcareer@qq.com.
authors.forename: Changan
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China; Department of Pediatrics, University of California, San Francisco, USA. Electronic address: dezhi.mu@ucsf.edu.
authors.forename: Dezhi
authors.initials: D
authors.lastname: Mu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D001921:Brain / Q000254:growth & development* / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000276:immunology* / Q000473:pathology; D008070:Lipopolysaccharides; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015213:Neuroimmunomodulation / Q000502:physiology; D009474:Neurons / Q000276:immunology / Q000473:pathology; D000066829:Neuroprotection / Q000502:physiology; D011494:Protein Kinases / Q000172:deficiency* / Q000235:genetics; D034741:RNA, Small Interfering; D011897:Random Allocation; D012097:Repressor Proteins / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D008070:Lipopolysaccharides; D011494:Protein Kinases; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D051844:alpha-Synuclein; D000099202:PTEN-Induced Putative Kinase; C497605:Snca protein, mouse; C525546:Tip30 protein, mouse
keywords: Apoptosis; Hypoxia-ischemia; Immature brain; Lipopolysaccharide; PINK1; α-Synuclein