Figure 1Figure 1
The vicious cycle of TDP-43-mediated proteostatic collapse. TDP-43 aggregates actively contribute to pathology rather than merely serving as passive metabolic waste. They sequester essential components of the UPS, such as ubiquitin and E2/E3 ligases, and disrupt the ALP by depleting related components (e.g., dynactin-1), which are essential for autophagosome-lysosomal fusion. This leads to a self-perpetuating “vicious cycle” in which TDP-43 disrupts the very complexes responsible for its clearance, thereby impairing autophagic flux. Created in BioRender. Angelo Jamerlan. (2025) https://BioRender.com/ .