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- Title
Mild MPP<sup>+</sup> exposure impairs autophagic degradation through a novel lysosomal acidity-independent mechanism.
- Authors
Miyara, Masatsugu; Kotake, Yaichiro; Tokunaga, Wataru; Sanoh, Seigo; Ohta, Shigeru
- 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.
- Subjects
PARKINSON'S disease treatment; LYSOSOMES; AUTOPHAGY; CELL death; CATHEPSIN D
- Publication
Journal of Neurochemistry, 2016, Vol 139, Issue 2, p294
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/jnc.13700