Mild MPP⁺ exposure-induced glucose starvation enhances autophagosome synthesis and impairs its degradation

Parkinson's disease (PD) is a prevalent neurodegenerative disorder, mainly characterised by the progressive loss of dopaminergic neurons. MPP⁺ has been widely used as a PD-related neurotoxin, and their reports suggested the several hypotheses for neuronal cell death. However, most of these hypotheses come from the studies about the acute MPP⁺ exposure. We previously revealed that mild MPP⁺ exposure (10 and 200 μM), which induces gradual cell death, impairs autophagosome degradation at 48 h. In the present study, we further investigated the specific events of mild MPP⁺ exposure and revealed that mild MPP⁺ exposure causes the cell death through glucose starvation, but not acute toxic model (2.5 and 5 mM). At 36 h after mild MPP⁺ exposure, autophagosome synthesis was enhanced owing to glucose starvation and continued to enhance until 48 h, despite impaired autophagosome degradation. Inhibition of autophagosome synthesis reduced mild MPP⁺-induced cell death. In conclusion, we clarified that glucose starvation-enhanced autophagosome synthesis occurs at an earlier stage than impaired autophagosome degradation and is important in mild MPP⁺ toxicity.