@article{9561c0181eb742719df8c39fc79272b8,
title = "Proteasomal inhibition by alpha-synuclein filaments and oligomers",
abstract = "A unifying feature of many neurodegenerative disorders is the accumulation of polyubiquitinated protein inclusions in dystrophic neurons, e.g. containing alpha-synuclein, which is suggestive of an insufficient proteasomal activity. We demonstrate that alpha-synuclein and 20 S proteasome components co-localize in Lewy bodies and show that subunits from 20 S proteasome particles, in contrast to subunits of the 19 S regulatory complex, bind efficiently to aggregated filamentous but not monomeric alpha-synuclein. Proteasome binding to insoluble alpha-synuclein filaments and soluble alpha-synuclein oligomers results in marked inhibition of its chymotrypsin-like hydrolytic activity through a non-competitive mechanism that is mimicked by model amyloid-Abeta peptide aggregates. Endogenous ligands of aggregated alpha-synuclein like heat shock protein 70 and glyceraldehyde-6-phosphate dehydrogenase bind filaments and inhibit their anti-proteasomal activity. The inhibitory effect of amyloid aggregates may thus be amenable to modulation by endogenous chaperones and possibly accessible for therapeutic intervention.",
keywords = "Chymotrypsin, Cysteine Endopeptidases, Dose-Response Relationship, Drug, Erythrocytes, HSP70 Heat-Shock Proteins, Humans, Immunohistochemistry, Lewy Bodies, Ligands, Microscopy, Confocal, Microscopy, Electron, Multienzyme Complexes, Nerve Tissue Proteins, Neurodegenerative Diseases, Neurons, Proteasome Endopeptidase Complex, Protein Binding, Recombinant Proteins, Synucleins, Time Factors, alpha-Synuclein",
author = "Evo Lindersson and Rasmus Beedholm and Peter H{\o}jrup and Torben Moos and WeiPing Gai and Hendil, {Klavs B} and Jensen, {Poul H}",
year = "2004",
doi = "10.1074/jbc.M306390200",
language = "English",
volume = "279",
pages = "12924--34",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology, Inc.",
}