Protein aggregation and the abnormal accumulation of aggregates are considered as common mechanisms of neurodegeneration such as Parkinson’s disease (PD). Ursolic acid (UA), a natural pentacyclic triterpenoid compound, has shown a protective activity in several experimental models of brain dysfunction through inhibiting oxidative stress and inflammatory responses and suppressing apoptotic signaling in the brain. In this study, we investigated whether UA promoted autophagic clearance of protein aggregates and attenuated the pathology and characteristic symptoms in PD mouse model. Mice were injected with rotenone (1 mg · kg−1 · d−1, i.p.) five times per week for 1 or 2 weeks. We showed that rotenone injection induced significant motor deficit and prodromal non-motor symptoms accompanied by a significant dopaminergic neuronal loss and the deposition of aggregated proteins such as p62 and ubiquitin in the substantia nigra and striatum. Co-injection of UA (10 mg · kg−1 · d−1, i.p.) ameliorated all the rotenone-induced pathological alterations. In differentiated human neuroblastoma SH-SY5Y cells, two-step treatment with a proteasome inhibitor MG132 (0.25, 2.5 μM) induced marked accumulation of ubiquitin and p62 with clear and larger aggresome formation, while UA (5 μM) significantly attenuated the MG132-induced protein accumulation. Furthermore, we demonstrated that UA (5 μM) significantly increased autophagic clearance by promoting autophagic flux in primary neuronal cells and SH-SY5Y cells; UA affected autophagy regulation by increasing the phosphorylation of JNK, which triggered the dissociation of Bcl-2 from Beclin 1. These results suggest that UA could be a promising therapeutic candidate for reducing PD progression from the prodromal stage by regulating abnormal protein accumulation in the brain.
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Does treatment with autophagy-enhancers and/or ROS-scavengers alleviate behavioral and neurochemical consequences of low-dose rotenone-induced mild mitochondrial dysfunction in mice?
Molecular Psychiatry Open Access 23 January 2023
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This work was supported by the GRRC program of Gyeonggi Province, Korea (GRRC-CHA2017-A01, Validity and Safety Evaluation of Regional Specialized Resources) and the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning, Korea (NRF-2016R1C1B1015991, NRF-2019R1H1A1080255, and NRF2021R1A2C1013180).
The authors declare no competing interests.
All animal care and experimental procedures complied with and were approved by the Institutional Animal Care and Use Committee (IACUC) of CHA University (IACUC190113, IACUC200111, and IACUC210106). The animal studies are reported in compliance with the ARRIVE guidelines . Every effort was made to minimize animal suffering and to perform the experiments using fewer mice.
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Bang, Y., Kwon, Y., Kim, M. et al. Ursolic acid enhances autophagic clearance and ameliorates motor and non-motor symptoms in Parkinson’s disease mice model. Acta Pharmacol Sin (2022). https://doi.org/10.1038/s41401-022-00988-2
- Parkinson’s disease
- SH-SY5Y cells
- ursolic acid