DGIST’s research team led by Dr. Yun-Il Lee in Well Aging Research Center has identified a new mechanism of inhibition of dopaminergic neuronal apoptosis and suggested the possibility of preventing and treating Parkinson’s disease.
Parkinson’s disease (PD) is a typical degenerative brain disease caused by the death of dopaminergic neurons in the middle cerebral blood. It is a disease with a higher incidence in the population aged 60 or older, exhibiting symptoms such as tremor, stiffness, slow motion and postural instability.
In particular, as the majority of Parkinson’s patients suffer from the progressive neurodegenerative disease, many researchers newly started to focus on cell death, a loss of dopamine-producing neurons, to treat PD. With regard to the cell death process, in vivo cell stress and damages activate PARP-1 (Poly ADP-ribose polymerase-1) and induce excessive accumulation of PAR (Poly ADP-ribose) and those activities activate AIF (Apoptosis-Inducing Factor), a factor that induces cell death, and destroy DNA. This new mechanism of cell death (Parthanatos) has recently been known as the cause of degenerative brain diseases such as Parkinson’s disease, stroke, heart attack, diabetes, etc. and the mechanism has been extensively studied as previous research to treat these diseases.
Currently, medications are being used to alleviate symptoms of Parkinson’s disease. However, there are no government-approved drugs that can inhibit dopaminergic neuronal cell death. Then, the research teams have found the possibility in licorice, the herb medicine.
Dr. Yun-Il Lee carried out joint research with Professor Joo-Ho Shin and Professor Yunjong Lee from Sungkyunkwan University School of Medicine to study candidate compounds for the treatment of Parkinson’s disease. For example, the researchers have identified the mechanism that cortisol, a stress hormone, promotes dopaminergic neuronal activity by inducing parkin protein expression that inhibits dopamine neuronal cell death.
In this study, the research teams found the candidate drugs that induce the expression of RNF146 protein involved in the inhibition of neuronal cell death through high-speed mass screening method using the natural materials library of the Natural Medicine Bank of Korea Foundation.
As a result, the study has confirmed that liquiritigenin, a licorice extract, induces the expression of RNF146 protein and removes excessively accumulated PAR binding and modified substrate proteins using the ubiquitin proteasome system and results in inhibition of dopamine neuronal cell death.
In addition, the research teams have been working on identifying the mechanism which induces liquiritigenin’s RNF146 protein expression and demonstrated that it regulates transcription through binding and activity with estrogen receptors in cell and animal models. Consequently, it has been scientifically proved that liquiritigenin, a licorice extract, can be used as a treatment for degenerative Parkinson’s disease.
Dr. Yun-Il Lee stated “Neuronal death is involved in a variety of signaling systems in vivo. Therefore, it is essential to identify a new mechanism that is able to control the system comprehensively and we have found additional possibilities in licorice extract.” He added “I would like to contribute to the treatment of degenerative brain diseases such as Parkinson’s disease by conducting advanced researches, comprehensive research and clinical studies.”
Source: Dajung Kim – DGIST
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited to Daegu Gyeongbuk Institute of Science and Technology (DGIST).
Original Research: Full open access research for “Estrogen receptor activation contributes to RNF146 expression and neuroprotection in Parkinson’s disease models” by Hyojung Kim, Sangwoo Ham, Joon Yeop Lee, Areum Jo, Gum Hwa Lee, Yun-Song Lee, MyoungLae Cho, Heung-Mook Shin, Donghoon Kim, Olga Pletnikova, Juan C. Troncoso, Joo-Ho Shin, Yun-Il Lee and Yunjong Lee in Oncotarget. Published online November 2017 doi:10.18632/oncotarget.21828
Estrogen receptor activation contributes to RNF146 expression and neuroprotection in Parkinson’s disease models
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.
“Estrogen receptor activation contributes to RNF146 expression and neuroprotection in Parkinson’s disease models” by Hyojung Kim, Sangwoo Ham, Joon Yeop Lee, Areum Jo, Gum Hwa Lee, Yun-Song Lee, MyoungLae Cho, Heung-Mook Shin, Donghoon Kim, Olga Pletnikova, Juan C. Troncoso, Joo-Ho Shin, Yun-Il Lee and Yunjong Lee in Oncotarget. Published online November 2017 doi:10.18632/oncotarget.21828