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

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 super(+) suggest autophagy involvement in the pathogenesis of PD, the effect of MPP super(+) on autophagic processes under mild exposure, which mimics the slow progressive nature of PD, remains largely unclear. We examined the effect of mild MPP super(+) 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 super(+) toxicity (2.5 and 5 mM for 24 h). In SH-SY5Y cells, mild MPP super(+) exposure predominantly inhibited autophagosome degradation, whereas acute MPP super(+) exposure inhibited both autophagosome degradation and basal autophagy. Mild MPP super(+) 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 super(+) exposure induced impaired autophagosome degradation and cell death, but did not prevent the pathogenic response to acute MPP super(+) exposure, suggesting irreversible lysosomal damage. We demonstrated impaired autophagic degradation by MPP super(+) exposure and mechanistic differences between mild and acute MPP super(+) toxicities. Mild MPP super(+) toxicity impaired autophagosome degradation through novel lysosomal acidity-independent mechanisms. Sustained mild lysosomal damage may contribute to PD. We examined the effects of MPP super(+) on autophagic processes under mild exposure, which mimics the slow progressive nature of Parkinson's disease, in SH-SY5Y cells. This study demonstrated impaired autophagic degradation through a reduction in lysosomal cathepsin D activity without altering lysosomal acidity by mild MPP super(+) exposure. Mechanistic differences between acute and mild MPP super(+) toxicity were also observed. Sustained mild damage of lysosome may be an underlying cause of Parkinson's disease. Cover Image for this issue: doi: . We examined the effects of MPP super(+) on autophagic processes under mild exposure, which mimics the slow progressive nature of Parkinson's disease, in SH-SY5Y cells. This study demonstrated impaired autophagic degradation through a reduction in lysosomal cathepsin D activity without altering lysosomal acidity by mild MPP super(+) exposure. Mechanistic