Fyn kinase regulates dopaminergic neuronal apoptosis in animal and cell models of high glucose (HG) treatment

BACKGROUND: High glucose (HG) is linked to dopaminergic neuron loss and related Parkinson's disease (PD), but the mechanism is unclear. RESULTS: Rats and differentiated SH-SY5Y cells were used to investigate the effect of HG on dopaminergic neuronal apoptotic death. We found that a 40-day HG diet elevated cleaved caspase 3 levels and activated Fyn and mTOR/S6K signaling in the substantia nigra of rats. In vitro, 6 days of HG treatment activated Fyn, enhanced binding between Fyn and mTOR, activated mTOR/S6K signaling, and induced neuronal apoptotic death. The proapoptotic effect of HG was rescued by either the Fyn inhibitor PP1 or the mTOR inhibitor rapamycin. PP1 inhibited mTOR/S6K signaling, but rapamycin was unable to modulate Fyn activation. CONCLUSIONS: HG induces dopaminergic neuronal apoptotic death via the Fyn/mTOR/S6K pathway.