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Estrogen receptor activation contributes to RNF146 expression and neuroprotection in Parkinson's disease models
- Estrogen receptor activation contributes to RNF146 expression and neuroprotection in Parkinson's disease models
- Kim, Hyo Jung; Ham, Sang Woo; Lee, Joon Yeop; Jo, Areum; Lee, Gum Hwa; Lee, Yun Song; Cho, Myoung Lae; Shin, Heung Mook; Kim, Dong Hoon; Pletnikova, Olga; Troncoso, Juan C; Shin, Joo Ho; Lee, Yun Il; Lee, Yun Jong
- DGIST Authors
- Lee, Yun Il
- Issue Date
- Oncotarget, 8(63), 106721-106739
- Article Type
- estrogen receptor; liquiritigenin; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1; oxidopamine; protein RNF146; ubiquitin protein ligase E3; unclassified drug; adult; aged; animal cell; animal experiment; animal model; animal tissue; Article; cell death; controlled study; embryo; enzyme activation; female; high throughput screening; human; human cell; human tissue; male; middle aged; mouse; nonhuman; Parkinson disease; pathogenesis; promoter region; protein expression; protein function; SH-SY5Y cell line; very elderly
- 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. © Kim et al.
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