Parkin deficiency exacerbate ethanol-induced dopaminergic neurodegeneration by P38 pathway dependent inhibition of autophagy and mitochondrial function
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 earl...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-04-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231716302440 |
| _version_ | 1818836367733424128 |
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| author | Chul Ju Hwang Young Eun Kim Dong Ju Son Mi Hee Park Dong-Young Choi Pil-Hoon Park Mats Hellström Sang-Bae Han Ki-Wan Oh Eun Kyung Park Jin Tae Hong |
| author_facet | Chul Ju Hwang Young Eun Kim Dong Ju Son Mi Hee Park Dong-Young Choi Pil-Hoon Park Mats Hellström Sang-Bae Han Ki-Wan Oh Eun Kyung Park Jin Tae Hong |
| author_sort | Chul Ju Hwang |
| collection | DOAJ |
| description | 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 (100 μM) in Park2 siRNA-transfacted PC12 cells (5 μM). 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 (10 μM) and in vivo 10 mg/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) |
| first_indexed | 2024-12-19T03:05:29Z |
| format | Article |
| id | doaj.art-953ba2f846cb4f188fe3f4f95be01638 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-19T03:05:29Z |
| publishDate | 2017-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-953ba2f846cb4f188fe3f4f95be016382022-12-21T20:38:08ZengElsevierRedox Biology2213-23172017-04-0111456468Parkin deficiency exacerbate ethanol-induced dopaminergic neurodegeneration by P38 pathway dependent inhibition of autophagy and mitochondrial functionChul Ju Hwang0Young Eun Kim1Dong Ju Son2Mi Hee Park3Dong-Young Choi4Pil-Hoon Park5Mats Hellström6Sang-Bae Han7Ki-Wan Oh8Eun Kyung Park9Jin Tae Hong10College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsangmyeong1-ro, Heungdeok-gu, Cheongju, Chungbuk 361-951, Republic of KoreaCollege of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsangmyeong1-ro, Heungdeok-gu, Cheongju, Chungbuk 361-951, Republic of KoreaCollege of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsangmyeong1-ro, Heungdeok-gu, Cheongju, Chungbuk 361-951, Republic of KoreaCollege of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsangmyeong1-ro, Heungdeok-gu, Cheongju, Chungbuk 361-951, Republic of KoreaCollege of Pharmacy, Yeungnam University, 280, Daehak-ro, Gyeongsan, Gyeongbuk 712-749, Republic of KoreaCollege of Pharmacy, Yeungnam University, 280, Daehak-ro, Gyeongsan, Gyeongbuk 712-749, Republic of KoreaLaboratory for Transplantation and Regenerative Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenCollege of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsangmyeong1-ro, Heungdeok-gu, Cheongju, Chungbuk 361-951, Republic of KoreaCollege of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsangmyeong1-ro, Heungdeok-gu, Cheongju, Chungbuk 361-951, Republic of KoreaDepartment 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; Corresponding authors.College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsangmyeong1-ro, Heungdeok-gu, Cheongju, Chungbuk 361-951, Republic of Korea; Corresponding authors.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 (100 μM) in Park2 siRNA-transfacted PC12 cells (5 μM). 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 (10 μM) and in vivo 10 mg/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)http://www.sciencedirect.com/science/article/pii/S2213231716302440 |
| spellingShingle | Chul Ju Hwang Young Eun Kim Dong Ju Son Mi Hee Park Dong-Young Choi Pil-Hoon Park Mats Hellström Sang-Bae Han Ki-Wan Oh Eun Kyung Park Jin Tae Hong Parkin deficiency exacerbate ethanol-induced dopaminergic neurodegeneration by P38 pathway dependent inhibition of autophagy and mitochondrial function Redox Biology |
| title | Parkin deficiency exacerbate ethanol-induced dopaminergic neurodegeneration by P38 pathway dependent inhibition of autophagy and mitochondrial function |
| title_full | Parkin deficiency exacerbate ethanol-induced dopaminergic neurodegeneration by P38 pathway dependent inhibition of autophagy and mitochondrial function |
| title_fullStr | Parkin deficiency exacerbate ethanol-induced dopaminergic neurodegeneration by P38 pathway dependent inhibition of autophagy and mitochondrial function |
| title_full_unstemmed | Parkin deficiency exacerbate ethanol-induced dopaminergic neurodegeneration by P38 pathway dependent inhibition of autophagy and mitochondrial function |
| title_short | Parkin deficiency exacerbate ethanol-induced dopaminergic neurodegeneration by P38 pathway dependent inhibition of autophagy and mitochondrial function |
| title_sort | parkin deficiency exacerbate ethanol induced dopaminergic neurodegeneration by p38 pathway dependent inhibition of autophagy and mitochondrial function |
| url | http://www.sciencedirect.com/science/article/pii/S2213231716302440 |
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