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

Abstract

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 μM 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. We examined the effects of MPP⁺ 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⁺ exposure. Mechanistic differences between acute and mild MPP⁺ toxicity were also observed. Sustained mild damage of lysosome may be an underlying cause of Parkinson's disease. Cover Image for this issue: doi: 10.1111/jnc.13338.

Keywords: MPP +; Parkinson's disease; autophagy; cathepsin D; lysosome.