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

• Published in: Journal of neurochemistry Vol. 139; no. 2; pp. 294 - 308
• Main Authors: Miyara, Masatsugu, Kotake, Yaichiro, Tokunaga, Wataru, Sanoh, Seigo, Ohta, Shigeru
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-10-2016
• Subjects: 1-Methyl-4-phenylpyridinium - antagonists & inhibitors; 1-Methyl-4-phenylpyridinium - toxicity; Acids; Autophagy; Autophagy - drug effects; cathepsin D; Cathepsin D - metabolism; Cell Death - drug effects; Cell Line; Dopamine Agents - toxicity; Humans; lysosome; Lysosomes - drug effects; MPP; Neurochemistry; Parkinson Disease, Secondary - chemically induced; Parkinson Disease, Secondary - pathology; Parkinson's disease; Phagosomes - drug effects; Sirolimus - pharmacology; Trehalose - pharmacology; Parkinson's disease; autophagy; cathepsin D; MPP; lysosome
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.13700

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.
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.