Protease-Mediated TAR DNA-Binding Protein 43 (TDP-43) Pathogenesis: From Molecular Mechanisms to Therapeutic Opportunities.

TDP-43 proteinopathy is the defining pathological feature in approximately 50% of frontotemporal lobar degeneration (FTLD) cases, yet the precise mechanism or biochemical transition from nuclear proteostasis to cytoplasmic toxicity remains a critical knowledge gap. While its role in repressing nonconserved cryptic exons is well reported, this review highlights and explores the synergy between site-specific proteolysis and post-translational modification (PTM)-induced phase transitions. We propose a mechanism where primary endoproteolytic cleavage by calpain, caspase, and asparaginyl endopeptidase acts as a "protease switch" to generate a C-terminal fragment that disturbs the nuclear import ability of TDP43. These fragments serve as preferred substrates for coordinated hyperphosphorylation and SUMOylation, which drive widespread transcriptome shutdown. We emphasize that synthesizing a small-molecule bridge between these proteins and TDP-43 reduces aberrant protease-mediated fragmentation and delocalization of many proteins. Therefore, in this review, we highlight several therapeutic drug discovery strategies to intercept TDP-43 at the preaggregation stage and restore its function, offering disease-modifying pathways.