title: Hydrocortisone-induced parkin prevents dopaminergic cell death via CREB pathway in Parkinson's disease model.
abstract: Dysfunctional parkin due to mutations or post-translational modifications contributes to dopaminergic neurodegeneration in Parkinson's disease (PD). Overexpression of parkin provides protection against cellular stresses and prevents dopamine cell loss in several PD animal models. Here we performed an unbiased high-throughput luciferase screening to identify chemicals that can increase parkin expression. Among promising parkin inducers, hydrocortisone possessed the most favorable profiles including parkin induction ability, cell protection ability, and physicochemical property of absorption, distribution, metabolism, and excretion (ADME) without inducing endoplasmic reticulum stress. We found that hydrocortisone-induced parkin expression was accountable for cell protection against oxidative stress. Hydrocortisone-activated parkin expression was mediated by CREB pathway since gRNA to CREB abolished hydrocortisone's ability to induce parkin. Finally, hydrocortisone treatment in mice increased brain parkin levels and prevented 6-hydroxy dopamine induced dopamine cell loss when assessed at 4 days after the toxin's injection. Our results showed that hydrocortisone could stimulate parkin expression via CREB pathway and the induced parkin expression was accountable for its neuroprotective effect. Since glucocorticoid is a physiological hormone, maintaining optimal levels of glucocorticoid might be a potential therapeutic or preventive strategy for Parkinson's disease.
authors.affiliation: Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, 440-746, Republic of Korea.
authors.forename: Sangwoo
authors.initials: S
authors.lastname: Ham
authors.affiliation: Well Aging Research Center, DGIST, Daegu, 42988, Republic of Korea. ylee56@dgist.ac.kr.|Companion Diagnostics and Medical Technology Research Group, DGIST, Daegu, 42988, Republic of Korea. ylee56@dgist.ac.kr.
authors.forename: Yun-Il
authors.initials: YI
authors.lastname: Lee
authors.affiliation: Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, 440-746, Republic of Korea.
authors.forename: Minkyung
authors.initials: M
authors.lastname: Jo
authors.affiliation: Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, 440-746, Republic of Korea.
authors.forename: Hyojung
authors.initials: H
authors.lastname: Kim
authors.affiliation: Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, 440-746, Republic of Korea.
authors.forename: Hojin
authors.initials: H
authors.lastname: Kang
authors.affiliation: Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, 440-746, Republic of Korea.
authors.forename: Areum
authors.initials: A
authors.lastname: Jo
authors.affiliation: College of Pharmacy, Chosun University, Gwangju, 501-759, Republic of Korea.
authors.forename: Gum Hwa
authors.initials: GH
authors.lastname: Lee
authors.affiliation: Well Aging Research Center, DGIST, Daegu, 42988, Republic of Korea.
authors.forename: Yun Jeong
authors.initials: YJ
authors.lastname: Mo
authors.affiliation: Well Aging Research Center, DGIST, Daegu, 42988, Republic of Korea.
authors.forename: Sang Chul
authors.initials: SC
authors.lastname: Park
authors.affiliation: Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, 440-746, Republic of Korea.
authors.forename: Yun Song
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, 440-746, Republic of Korea. jshin24@skku.edu.|Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, 440-746, Republic of Korea. jshin24@skku.edu.
authors.forename: Joo-Ho
authors.initials: JH
authors.lastname: Shin
authors.affiliation: Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, 440-746, Republic of Korea. ylee69@skku.edu.
authors.forename: Yunjong
authors.identifier: http://orcid.org/0000-0003-0182-2279
authors.initials: Y
authors.lastname: Lee
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D055808:Drug Discovery; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D057166:High-Throughput Screening Assays; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism* / Q000494:pharmacology; D007150:Immunohistochemistry; D051379:Mice; D008954:Models, Biological; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D006854:Hydrocortisone