Mild MPP+ exposure impairs autophagic degradation through a novel lysosomal acidity-independent mechanism

摘要

Parkinson's disease (PD) is the second most common neurodegenerative disorder, but its underlying cause remains unknown. Although recent studies using PD-related neurotoxin MPP+ suggest autophagy involvement in the pathogenesis of PD, the effect of MPP+ on autophagic processes under mild exposure, which mimics the slow progressive nature of PD, remains largely unclear. We examined the effect of mild MPP+ exposure (10 and 200 mu M for 48 h), which induces a more slowly developing cell death, on autophagic processes and the mechanistic differences with acute MPP+ toxicity (2.5 and 5 mM for 24 h). In SH-SY5Y cells, mild MPP+ exposure predominantly inhibited autophagosome degradation, whereas acute MPP+ exposure inhibited both autophagosome degradation and basal autophagy. Mild MPP+ exposure reduced lysosomal hydrolase cathepsin D activity without changing lysosomal acidity, whereas acute exposure decreased lysosomal density. Lysosome biogenesis enhancers trehalose and rapamycin partially alleviated mild MPP+ exposure induced impaired autophagosome degradation and cell death, but did not prevent the pathogenic response to acute MPP+ exposure, suggesting irreversible lysosomal damage. We demonstrated impaired autophagic degradation by MPP+ exposure and mechanistic differences between mild and acute MPP+ toxicities. Mild MPP+ toxicity impaired autophagosome degradation through novel lysosomal acidity- independent mechanisms. Sustained mild lysosomal damage may contribute to PD.