Proteasomal inhibition by α-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.