Mild MPP+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+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.
Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.|Global Career Design Center, Hiroshima University, Hiroshima, Japan.
Masatsugu
M
Miyara
Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. yaichiro@hiroshima-u.ac.jp.
Yaichiro
Y
Kotake
Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Wataru
W
Tokunaga
Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Seigo
S
Sanoh
Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Shigeru
S
Ohta
D015655:1-Methyl-4-phenylpyridinium / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000143:Acids; D001343:Autophagy / Q000187:drug effects*; D002402:Cathepsin D / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D015259:Dopamine Agents / Q000633:toxicity*; D006801:Humans; D008247:Lysosomes / Q000187:drug effects*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000473:pathology; D010588:Phagosomes / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D014199:Trehalose / Q000494:pharmacology
D000143:Acids; D015259:Dopamine Agents; D014199:Trehalose; D002402:Cathepsin D; D015655:1-Methyl-4-phenylpyridinium; D020123:Sirolimus

MPP
+
; Parkinson's disease; autophagy; cathepsin D; lysosome