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(American Journal of Pathology. 2007;170:75-86.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060524

Regulation of Autophagy by Extracellular Signal-Regulated Protein Kinases During 1-Methyl-4-Phenylpyridinium-Induced Cell Death

Jian-hui Zhu^*, Craig Horbinski^*, Fengli Guo, Simon Watkins, Yasuo Uchiyama and Charleen T. Chu^*

From the Department of Pathology/Division of Neuropathology, Pittsburgh Institute for Neurodegenerative Diseases, and Center for Neuroscience,^* and Department of Cell Biology and Physiology and Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Department of Cell Biology and Neuroscience, Osaka University Graduate School of Medicine, Osaka, Japan

Increased autophagic vacuoles (AVs) occur in injured or degenerating neurons, under both developmental and pathological situations. Although regulation of starvation-induced autophagy has been extensively studied, less is known about autophagic responses to pathological damage. The neurotoxin 1-methyl-4-phenylpyridinium (MPP⁺) produces mitochondria-targeted injury, which contributes to parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine in mammals. Here, we demonstrate that MPP⁺ elicited increased autophagy in SH-SY5Y cells, as assessed by electron microscopy, immunofluorescence for the autophagy protein LC3/Atg8, LC3 electrophoretic mobility shift, mitochondrial degradation, and monodansylcadaverine staining for late AVs/autolysosomes. During nutrient deprivation, class III phosphatidylinositol-3 kinase (PI3K) stimulates autophagy in concert with the autophagy-regulatory protein beclin 1/Atg6. Although PI3K inhibitors and RNA interference knockdown of beclin 1 effectively inhibited autophagy elicited by amino acid deprivation, neither reduced MPP⁺-induced autophagic stress. In contrast, inhibition of mitogen-activated protein kinase/extracellular signal-regulated protein kinase kinase reduced AV content, mitochondrial degradation, and cell death in MPP⁺-treated cells. RNA interference studies targeting core Atg proteins also reduced AV content and cell death. Likewise, in primary midbrain dopaminergic neurons, MPP⁺ elicited increased AV content, which was reversed by inhibition of mitogen-activated protein kinase/extracellular signal-regulated protein kinase kinase but not PI3K. These results implicate a role for extracellular signal-regulated protein kinase (ERK) signaling upstream of MPP⁺-elicited autophagic stress. Moreover, pathological stimulation of beclin 1-independent autophagy is associated with neuronal cell death.

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