Ursolic acid enhances autophagic clearance and ameliorates motor and non-motor symptoms in Parkinson’s disease mice model

Yeojin Bang1, Yoonjung Kwon1, Mihyang Kim1, Soung Hee Moon1, Kiwon Jung1, Hyun Jin Choi1
1 College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Pocheon, Gyeonggi-do 11160, South Korea
Correspondence to: Hyun Jin Choi:,
DOI: 10.1038/s41401-022-00988-2
Received: 23 March 2022
Accepted: 22 August 2022
Advance online: 22 September 2022


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.
Keywords: autophagy; JNK; Parkinson’s disease; rotenone; SH-SY5Y cells; ursolic acid

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