SummaryBackground and aimsTenuigenin (Ten) is a Chinese herbal extract with antioxidative and antiinflammatory effects on toxin‐induced cell models of Parkinson's disease (PD); however, its effects on α‐synuclein toxicity‐based PD models remain unknown. α‐synuclein hyperphosphorylation is a key event in PD pathogenesis and potential target of therapeutic interventions. We tested whether Ten alleviates α‐synuclein‐induced cytotoxicity via reducing kinases that phosphorylate α‐synuclein.MethodsSH‐SY5Y cells transiently transfected with wild‐type or A53T mutant α‐synuclein were used to evaluate the effect of Ten on the levels of α‐synuclein phosphorylation‐related kinases. Cells treated with 10 μM Ten for 24 h were measured for viability (proliferation and apoptosis assays) and cellular proteins harvested and fractioned. The levels of total and phosphorylated α‐synuclein and five associated kinases (polo‐like kinase [PLK] 1–3, casein kinase [CK] 1–2) were evaluated by Western blotting.ResultsOverexpression of either wild‐type or A53T mutant α‐synuclein decreased cell viability and increased α‐synuclein phosphorylation. Ten treatment‐protected cells from this α‐synuclein‐induced toxicity and dramatically reduced α‐synuclein phosphorylation and PLK3 (but not other kinase) levels.ConclusionIn α‐synuclein cell model of PD, Ten is effective in attenuating α‐synuclein‐induced toxicity and α‐synuclein phosphorylation probably via targeting PLK3, suggesting it could be an efficient therapeutic drug to treat α‐synuclein‐related neurodegeneration.