title: Parkin deficiency exacerbate ethanol-induced dopaminergic neurodegeneration by P38 pathway dependent inhibition of autophagy and mitochondrial function.
abstract: Parkinson's disease (PD) is a neurodegenerative disease characterized by selective degeneration of dopaminergic neurons in the substantia nigra. Parkin (which encoded by Park2), an E3 ubiquitin ligase, is the most frequently mutated gene that has casually been linked to autosomal recessive early onset familial PD. We tested the effect of Park2 on ethanol-induced dopaminergic neurodegeneration in Park2 knockout (KO) transgenic mice after chronic ethanol feeding. Male Park2 wild type (WT) and KO mice (8 weeks old) were fed on a Lieber-DeCarli diet containing 6.6% ethanol for 2 weeks, and compared their responses. We found that knockout of Park2 exacerbates ethanol-induced behavioral impairment as well as dopamine depletion. In the mechanism study, we found that knockout of Park2 increased reactive oxygen species (ROS) production, mitophagy formation, mitochondrial dysfunction, and expression of pro-apoptotic proteins, but decreased expression of pro-autophagic proteins. Knockout of Park2 also increased ethanol-induced activation of p38 mitogen-activated protein kinase. In addition, ROS production, mitophagy formation, mitochondrial dysfunction, and expression of pro-apoptotic proteins were increased, but expression of pro-autophagic proteins were decreased by a treatment of ethanol (100μM) in Park2 siRNA-transfacted PC12 cells (5μM). Moreover, the exacerbating effects of Park2 deletion on ethanol-induced ROS generation, mitophagy, mitochondrial dysfunction as well as cell death were reduced by p38 specific inhibitor (SB203580) in in vitro (10μM) and in vivo 10mg/kg). Park2 deficiency exacerbates ethanol-induced dopaminergic neuron damage through p38 kinase dependent inhibition of autophagy and mitochondrial function.
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsangmyeong1-ro, Heungdeok-gu, Cheongju, Chungbuk 361-951, Republic of Korea.
authors.forename: Chul Ju
authors.initials: CJ
authors.lastname: Hwang
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsangmyeong1-ro, Heungdeok-gu, Cheongju, Chungbuk 361-951, Republic of Korea.
authors.forename: Young Eun
authors.initials: YE
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsangmyeong1-ro, Heungdeok-gu, Cheongju, Chungbuk 361-951, Republic of Korea.
authors.forename: Dong Ju
authors.initials: DJ
authors.lastname: Son
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsangmyeong1-ro, Heungdeok-gu, Cheongju, Chungbuk 361-951, Republic of Korea.
authors.forename: Mi Hee
authors.initials: MH
authors.lastname: Park
authors.affiliation: College of Pharmacy, Yeungnam University, 280, Daehak-ro, Gyeongsan, Gyeongbuk 712-749, Republic of Korea.
authors.forename: Dong-Young
authors.initials: DY
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Yeungnam University, 280, Daehak-ro, Gyeongsan, Gyeongbuk 712-749, Republic of Korea.
authors.forename: Pil-Hoon
authors.initials: PH
authors.lastname: Park
authors.affiliation: Laboratory for Transplantation and Regenerative Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Hellström
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsangmyeong1-ro, Heungdeok-gu, Cheongju, Chungbuk 361-951, Republic of Korea.
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Han
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsangmyeong1-ro, Heungdeok-gu, Cheongju, Chungbuk 361-951, Republic of Korea.
authors.forename: Ki-Wan
authors.initials: KW
authors.lastname: Oh
authors.affiliation: Department of Obstetrics and Gynecology, College of Medicine, Daejeon St. Mary's Hospital, The Catholic University of Korea, 64 Daeheung-ro, Jung-gu, Daejeon 34943, Rep. of Korea.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Park
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsangmyeong1-ro, Heungdeok-gu, Cheongju, Chungbuk 361-951, Republic of Korea. Electronic address: jinthong@chungbuk.ac.kr.
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
mesh_terms: D000818:Animals; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology; D000431:Ethanol / Q000008:administration & dosage; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D063306:Mitophagy / Q000187:drug effects; D016716:PC12 Cells; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011725:Pyridines / Q000008:administration & dosage; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D007093:Imidazoles; D011725:Pyridines; D017382:Reactive Oxygen Species; D000431:Ethanol; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580
keywords: Autophagy; Mitochondrial function; Neurodegeneration; Park2; Parkinson disease (PD)