Figure 3.

Schematic of transactivation response DNA-binding protein 43 (TDP-43) proteolysis by calpain and caspase-3 pathways. In this model, caspase cleaves at the N-terminal (Asp89 ↓Ala90, Asp219 ↓Val220, based on Zhang YJ, et al⁷) producing caspase-dependent CTFs at 33 and 2 5 kDa and unknown C-terminal cleavage sites generate fragments of 39 and 12 kDa. However, calpain cleaves at least six sites (Phe229↓Ala230; Leu243↓Cys244; Gln286↓Gly287; Gly295↓Gly296; Ala297↓Gly298; Met323↓Ala324, based on Yamashita T, et al¹²) producing multiple fragments. But the cleavage sites generating major calpain-specific C-terminal fragments (CTFs) of 39 and 35 kDa remain unknown.