Fig. 1

Mechanism for degradation of TDP-43 aggregates by PROTAC molecules. A The PROTAC binds E3 ligase and TDP-43 aggregates simultaneously to facilitate the transfer of ubiquitins to TDP-43 aggregates. As ubiquitin chains on TDP-43 aggregates are recognized by proteasome, TDP-43 aggregates are degraded. BTA: benzothiazole-aniline derivative. B The synthetic process of PROTACs 1–4. Reagents and reaction conditions: (i) Pd(dppf)Cl₂, K₂CO₃, DMF, 80 °C, 18 h; 60%. (ii) BBr₃, CH₂Cl₂, 0 °C, 20 h; 98%. (iii) For 9a, N₃CH₂CH₂(OCH₂CH₂)OMs, K₂CO₃, DMF, 80 °C, 21 h; then PPh₃, THF, rt, 24 h; 50% overall yield. (iv) i-Pr₂NEt, NMP, 90 °C, 16–18 h; 32%. For the synthesis of 9b–9d, see experimental section