Proteasomal inhibition by alpha-synuclein filaments and oligomers.
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.
Lindersson
Evo
E
Department of Medical Biochemistry, University of Aarhus, 8000 Aarhus-C, Denmark.
Beedholm
Rasmus
R
Højrup
Peter
P
Moos
Torben
T
Gai
WeiPing
W
Hendil
Klavs B
KB
Jensen
Poul H
PH
D002918:Chymotrypsin / Q000737:chemistry; D003546:Cysteine Endopeptidases / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D016631:Lewy Bodies / Q000378:metabolism; D008024:Ligands; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry; D051843:Synucleins; D013997:Time Factors; D051844:alpha-Synuclein
D018840:HSP70 Heat-Shock Proteins; D008024:Ligands; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D002918:Chymotrypsin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex