Estrogen receptor activation contributes to RNF146 expression and neuroprotection in Parkinson's disease models
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Hyojung Kim1, Sangwoo Ham1, Joon Yeop Lee2, Areum Jo1, Gum Hwa Lee3, Yun-Song Lee1, MyoungLae Cho2, Heung-Mook Shin2, Donghoon Kim4, Olga Pletnikova5, Juan C. Troncoso4,5, Joo-Ho Shin1,6,*, Yun-Il Lee7,8,* and Yunjong Lee1,*
1Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 440-746, Republic of Korea
2National Development Institute of Korean Medicine, Gyeongsan 38540, Republic of Korea
3College of Pharmacy, Chosun University, Gwangju 501-759, Republic of Korea
4Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
5Department of Pathology, Division of Neuropathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
6Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-Do 440-746, Republic of Korea
7Well Aging Research Center, Daegu Geongbuk Institute of Science and Technology, Daegu 42988, South Korea
8Companion Diagnostics and Medical Technology Research Group, Daegu Geongbuk Institute of Science and Technology, Daegu 42988, South Korea
*These authors contributed equally to this work
Yunjong Lee, email: [email protected]
Yun-Il Lee, email: [email protected]
Joo-Ho Shin, email: [email protected]
Keywords: luciferase screen, preconditioning, RNF146, AIMP2, PARP1-dependent cell death
Received: April 19, 2017 Accepted: September 23, 2017 Published: October 11, 2017
RNF146 is an E3 ubiquitin ligase that specifically recognizes and polyubiquitinates poly (ADP-ribose) (PAR)-conjugated substrates for proteasomal degradation. RNF146 has been shown to be neuroprotective against PAR polymerase-1 (PARP1)-induced cell death during stroke. Here we report that RNF146 expression and RNF146 inducers can prevent cell death elicited by Parkinson’s disease (PD)-associated and PARP1-activating stimuli. In SH-SY5Y cells, RNF146 expression conferred resistance to toxic stimuli that lead to PARP1 activation. High-throughput screen using a luciferase construct harboring the RNF146 promoter identified liquiritigenin as an RNF146 inducer. We found that RNF146 expression by liquiritigenin was mediated by estrogen receptor activation and contributed to cytoprotective effect of liquiritigenin. Finally, RNF146 expression by liquiritigenin in mouse brains provided dopaminergic neuroprotection in a 6-hydroxydopamine PD mouse model. Given the presence of PARP1 activity and RNF146 deficits in PD, it could be a potential therapeutic strategy to restore RNF146 expression by natural compounds or estrogen receptor activation.
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