| Abstract | 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. |
| Authors | Jian-Hui Zhu, Craig Horbinski, Fengli Guo, Simon Watkins, Yasuo Uchiyama, Charleen T Chu
(Affiliation: Department of Pathology/Division of Neuropathology, Pittsburgh Institute for Neurodegenerative Diseases, Center for Biologic Imaging, Pittsburgh, PA, USA.)
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| Journal | The American journal of pathology
(Am J Pathol)
Vol. 170
Issue 1
Pg. 75-86
(Jan 2007)
ISSN: 0002-9440 United States |
| PMID | 17200184
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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| Chemical References |
- Apoptosis Regulatory Proteins
- BECN1 protein, human
- Becn1 protein, mouse
- Membrane Proteins
- Proteins
- 1-Methyl-4-phenylpyridinium
- 1-Phosphatidylinositol 3-Kinase
- Extracellular Signal-Regulated MAP Kinases
|
| Topics |
- 1-Methyl-4-phenylpyridinium
(pharmacology)
- 1-Phosphatidylinositol 3-Kinase
(metabolism)
- Animals
- Apoptosis Regulatory Proteins
(antagonists & inhibitors, metabolism)
- Autophagy
(drug effects)
- Cell Line, Tumor
- Extracellular Signal-Regulated MAP Kinases
(metabolism)
- Humans
- MAP Kinase Signaling System
(drug effects)
- Membrane Proteins
(antagonists & inhibitors, metabolism)
- Mesencephalon
(metabolism, pathology)
- Mice
- Mice, Inbred C57BL
- Neurons
(metabolism, pathology)
- Proteins
(antagonists & inhibitors, metabolism)
- RNA Interference
- Signal Transduction
(drug effects)
|
