Filamentous Aggregates Are Fragmented by the Proteasome Holoenzyme

• Published in: Cell reports (Cambridge) 2019-02, Vol.26 (8), p.2140-2149.e3
• Main Authors: Cliffe, Rachel, Sang, Jason C., Kundel, Franziska, Finley, Daniel, Klenerman, David, Ye, Yu
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphatases - metabolism; alpha-synuclein; Amyloid - metabolism; disaggregation; HEK293 Cells; Humans; proteasome; Proteasome Endopeptidase Complex - metabolism; protein aggregation; Proteolysis; tau; tau Proteins - metabolism; total-internal reflection fluorescence microscopy
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.01.096

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. [Display omitted] •The proteasome fragments tau and α-synuclein fibrils into small aggregates•Single-aggregate imaging was used to quantify changes in fibril and aggregate size•Fibril fragmentation depends on proteasomal ATPase but not proteolytic activity•Fragmented aggregate species induce cell death more potently than fibrils 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.