Regulation of autophagy by extracellular signal-regulated protein kinases during 1-methyl-4-phenylpyridinium-induced cell death.
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.[1]References
- Regulation of autophagy by extracellular signal-regulated protein kinases during 1-methyl-4-phenylpyridinium-induced cell death. Zhu, J.H., Horbinski, C., Guo, F., Watkins, S., Uchiyama, Y., Chu, C.T. Am. J. Pathol. (2007) [Pubmed]
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