한빛사 논문
Areum Jo1,2,†, Yunjong Lee1,2,3,4,5,6,†, Tae-In Kam2,4,†, Sung-Ung Kang2,4,5,6, Stewart Neifert2,4,5,6, Senthilkumar S. Karuppagounder2,4,5,6, Rin Khang1, Hojin Kang1,2, Hyejin Park2,4, Shih-Ching Chou2,5,6,7, Sungtaek Oh2,4, Haisong Jiang2,4,5,6, Deborah A. Swing8, Sangwoo Ham1, Sheila Pirooznia2,4,5,6, George K. E. Umanah2,4,5,6,‡, Xiaobo Mao2,4,5,6, Manoj Kumar2,4,5, Han Seok Ko2,4,5,6, Ho Chul Kang9, Byoung Dae Lee10, Yun-Il Lee2,4,§, Shaida A. Andrabi2,4,∥, Chi-Hu Park11,¶, Ji-Yeong Lee1, Hanna Kim1, Hyein Kim1,11, Hyojung Kim1, Jin Whan Cho12, Sun Ha Paek13, Chan Hyun Na2,4, Lino Tessarollo8, Valina L. Dawson2,3,4,5,6,14, Ted M. Dawson2,4,5,6,7,14,*,# and Joo-Ho Shin1,2,4,15,*,#
1Department of Pharmacology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, South Korea.
2Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
3Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
4Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
5Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
6Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA.
7Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
8Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21705, USA.
9Department of Physiology, Ajou University School of Medicine, Suwon 16499, South Korea.
10Neurodegeneration Control Research Center, Department of Neuroscience, Department of Physiology, Kyung Hee University School of Medicine, Seoul 02447, South Korea.
11Research Core Facility, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, South Korea.
12Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.
13Department of Neurosurgery, Seoul National University College of Medicine, Seoul 03080, South Korea.
14Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
15Samsung Medical Center, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Seoul 06351, South Korea.
*Corresponding author.
†These authors contributed equally to this work.
‡Present Address: Division of Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
§Present Address: Well Aging Research Center, Division of Biotechnology, Daegu Geongbuk Institute of Science and Technology (DGIST), Daegu 42988, South Korea.
∥Present address: Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
¶Present Address: Natural Bioactive and Anticancer Research Institute, YEPBio Co. Ltd. Anyang 14056, South Korea.
#These authors contributed equally to this work.
Abstract
Accumulation of the parkin-interacting substrate (PARIS; ZNF746), due to inactivation of parkin, contributes to Parkinson’s disease (PD) through repression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α; PPARGC1A) activity. Here, we identify farnesol as an inhibitor of PARIS. Farnesol promoted the farnesylation of PARIS, preventing its repression of PGC-1α via decreasing PARIS occupancy on the PPARGC1A promoter. Farnesol prevented dopaminergic neuronal loss and behavioral deficits via farnesylation of PARIS in PARIS transgenic mice, ventral midbrain transduction of AAV-PARIS, adult conditional parkin KO mice, and the α-synuclein preformed fibril model of sporadic PD. PARIS farnesylation is decreased in the substantia nigra of patients with PD, suggesting that reduced farnesylation of PARIS may play a role in PD. Thus, farnesol may be beneficial in the treatment of PD by enhancing the farnesylation of PARIS and restoring PGC-1α activity.
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