Tenuigenin Attenuates α‐Synuclein‐Induced Cytotoxicity by Down‐Regulating Polo‐Like Kinase 3

Abstract

Tenuigenin (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. SH-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. Overexpression 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. In 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.