FibrilPaint20 directs the ubiquitin-proteasome system to Tau amyloid fibrils

Failure of the Protein Quality Control (PQC) System to control the Tau protein leads to amyloid fibrils that are at the basis of various Tauopathies, including Alzheimers Disease (AD). Reinstating the PQC for Tau is desirable. Here we show that the PROTAC peptide FibrilPaint20 (FP20) recruits the ubiquitination system to Tau amyloid fibrils. We reconstituted the ubiquitin-proteasome cascade and monitored the stepwise ubiquitin transfer using the microfluidics technique FIDA. To direct ubiquitination specifically to amyloids, we discovered FP20, a bifunctional peptide that connects amyloid fibrils to the E3 ligase CHIP. FP20 mediated ubiquitination of recombinant and patient derived fibrils from various tauopathies, ultimately enabling the 26S proteasome to target CHIP-ubiquitinated Tau fibrils. This shows that FP20 cooperates with the PQC system and can initiate fibril cleavage. This offers a strategy to target amyloid diseases by cooperation with the PQC system exploiting key cellular systems.