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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.

Original publication




Journal article



Publication Date





22 - 26


Cysteine Endopeptidases, DNA, Complementary, Humans, Immunoblotting, Immunohistochemistry, Microscopy, Electron, Multienzyme Complexes, Nerve Tissue Proteins, Parkinson Disease, Plasmids, Proteasome Endopeptidase Complex, Protein Binding, Protein Denaturation, Protein Folding, Recombinant Proteins, Synucleins, Time Factors, Transfection, Tumor Cells, Cultured, Ubiquitin, alpha-Synuclein