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Poul Henning Jensen

Proteasomal inhibition by alpha-synuclein filaments and oligomers

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  • Evo Lindersson, Denmark
  • Rasmus Beedholm, Denmark
  • Peter Højrup, Denmark
  • Torben Moos, Denmark
  • WeiPing Gai, Denmark
  • Klavs B Hendil, Denmark
  • Poul H Jensen
  • Department of Medical Biochemistry
  • Interdisciplinary Nanoscience Center
  • Klinisk Immunologi, Aalborg Sygehus
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.
Original languageEnglish
JournalJournal of Biological Chemistry
Pages (from-to)12924-34
Number of pages10
Publication statusPublished - 2004

    Research areas

  • 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

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