Abstract
Alpha-synuclein (alpha-SN) is a ubiquitous protein that is especially abundant in the brain and has been postulated to play a central role in the pathogenesis of Parkinson's disease, Alzheimer's disease, and other neurodegenerative disorders. However, little is known about the neuronal functions of alpha-SN and the molecular and cellular mechanisms underlying neuronal loss. Here, we show that alpha-SN plays dual roles of neuroprotection and neurotoxicity depending on its concentration or level of expression. At nanomolar concentrations, a-SN protected neurons against serum deprivation, oxidative stress, and excitotoxicity through the PI3/Akt signaling pathway, and its protective effect was increased by Bcl-2 overexpression. Conversely, at both low micromolar and overexpressed levels in the cell, alpha-SN resulted in cytotoxicity. This might be related to decreased Bcl-xL expression and increased bax expression, which is subsequently followed by cytochrome c release and caspase activation and also by microglia-mediated inflammatory responses via the NFkappaB and mitogen-activated protein kinase pathways.
MeSH terms
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Animals
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Blotting, Western
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Cell Line
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Cell Survival / drug effects*
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Cells, Cultured
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Chromones / pharmacology
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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Gene Expression Regulation / drug effects
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Humans
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Imidazoles / pharmacology
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Morpholines / pharmacology
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NG-Nitroarginine Methyl Ester / pharmacology
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Nerve Tissue Proteins / pharmacology*
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Neurons / cytology
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Neurons / drug effects*
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Neurons / metabolism
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Nitric Oxide / metabolism
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Nitric Oxide Synthase / antagonists & inhibitors
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Nitric Oxide Synthase / metabolism
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Nitric Oxide Synthase Type II
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PC12 Cells
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoinositide-3 Kinase Inhibitors
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Pyridines / pharmacology
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RNA, Messenger / drug effects
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Rats
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Signal Transduction / drug effects
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Synucleins
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Time Factors
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Tumor Cells, Cultured
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alpha-Synuclein
Substances
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Chromones
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Enzyme Inhibitors
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Flavonoids
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Imidazoles
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Morpholines
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Nerve Tissue Proteins
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Pyridines
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RNA, Messenger
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SNCA protein, human
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Snca protein, rat
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Synucleins
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alpha-Synuclein
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Nitric Oxide
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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NOS2 protein, human
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Nos2 protein, rat
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AKT1 protein, human
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Akt1 protein, rat
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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SB 203580
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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NG-Nitroarginine Methyl Ester