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Redox Biol. 2017 Apr;11:456-468. doi: 10.1016/j.redox.2016.12.008. Epub 2016 Dec 8.

Parkin deficiency exacerbate ethanol-induced dopaminergic neurodegeneration by P38 pathway dependent inhibition of autophagy and mitochondrial function.

Author information

1
College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsangmyeong1-ro, Heungdeok-gu, Cheongju, Chungbuk 361-951, Republic of Korea.
2
College of Pharmacy, Yeungnam University, 280, Daehak-ro, Gyeongsan, Gyeongbuk 712-749, Republic of Korea.
3
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.
4
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.
5
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.

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.

KEYWORDS:

Autophagy; Mitochondrial function; Neurodegeneration; Park2; Parkinson disease (PD)

PMID:
28086194
PMCID:
PMC5226672
DOI:
10.1016/j.redox.2016.12.008
[Indexed for MEDLINE]
Free PMC Article

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