alpha-synuclein metabolism and aggregation is linked to ubiquitin-independent degradation by the proteasome.
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.
Tofaris
G K
GK
Cambridge Centre for Brain Repair and Neurology Department, University of Cambridge, Forvie Site, Robinson Way, CB2 2PY, Cambridge, UK.
Layfield
R
R
Spillantini
M G
MG
D003546:Cysteine Endopeptidases / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008854:Microscopy, Electron; D009097:Multienzyme Complexes / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D011489:Protein Denaturation; D017510:Protein Folding; D011994:Recombinant Proteins / Q000378:metabolism; D051843:Synucleins; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism*; D051844:alpha-Synuclein
D018076:DNA, Complementary; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C497604:SNCA protein, human; D051843:Synucleins; D025801:Ubiquitin; D051844:alpha-Synuclein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex