Abstract
alpha-Synuclein has been implicated in the pathogenesis of Parkinson's disease based on mutations in familial cases of the disease and its presence in Lewy bodies. Here we show that over-expression of wild-type human alpha-synuclein is sufficient to induce inclusion formation in SH-SY5Y cells. In this cellular model, proteasome inhibition leads to an increase of alpha-synuclein accumulation in vivo without ubiquitylation. In accordance, we find that in vitro, unmodified alpha-synuclein can be directly degraded by the 20S proteasome. These findings suggest an ubiquitin-independent mechanism of proteasomal degradation for alpha-synuclein and other natively unfolded proteins.
MeSH terms
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Cysteine Endopeptidases / metabolism*
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DNA, Complementary / metabolism
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Humans
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Immunoblotting
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Immunohistochemistry
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Microscopy, Electron
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Multienzyme Complexes / metabolism*
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Nerve Tissue Proteins / metabolism*
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Parkinson Disease / metabolism
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Plasmids / metabolism
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Proteasome Endopeptidase Complex
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Protein Binding
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Protein Denaturation
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Protein Folding
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Recombinant Proteins / metabolism
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Synucleins
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Time Factors
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Transfection
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Tumor Cells, Cultured
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Ubiquitin / metabolism*
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alpha-Synuclein
Substances
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DNA, Complementary
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Multienzyme Complexes
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Nerve Tissue Proteins
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Recombinant Proteins
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SNCA protein, human
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Synucleins
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Ubiquitin
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alpha-Synuclein
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex