Filamentous Aggregates Are Fragmented by the Proteasome Holoenzyme

Abstract

Summary: Filamentous aggregates (fibrils) are regarded as the final stage in the assembly of amyloidogenic proteins and are formed in many neurodegenerative diseases. Accumulation of aggregates occurs as a result of an imbalance between their formation and removal. Here we use single-aggregate imaging to show that large fibrils assembled from full-length tau are substrates of the 26S proteasome holoenzyme, which fragments them into small aggregates. Interestingly, although degradation of monomeric tau is not inhibited by adenosine 5’-(3-thiotriphosphate) (ATPγS), fibril fragmentation is predominantly dependent on the ATPase activity of the proteasome. The proteasome holoenzyme also targets fibrils assembled from α-synuclein, suggesting that its fibril-fragmenting function may be a general mechanism. The fragmented species produced by the proteasome shows significant toxicity to human cell lines compared with intact fibrils. Together, our results indicate that the proteasome holoenzyme possesses a fragmentation function that disassembles large fibrils into smaller and more cytotoxic species. : Cliffe et al. show that the proteasome holoenzyme can fragment fibrils assembled from tau and α-synuclein, both of which are associated with neurodegenerative disease. The fragmented aggregate species are structurally distinct from fibrils and more toxic than fibrils when added to cultured cells. Keywords: protein aggregation, tau, proteasome, alpha-synuclein, disaggregation, total-internal reflection fluorescence microscopy