TDP43 is regulated through transcriptional and posttranslational mechanisms. (A) TARDBP splicing is regulated not just by TDP43 but by other RNA-binding proteins. The TARDBP transcript undergoes alternative splicing to generate multiple isoforms through a process tightly controlled by several RNA-binding proteins. hnRNP A1 promotes production of marginal peptide (MP)13 (C-terminal tail: FISFQFMEEALH). Via conventional autoregulation, TDP43 facilitates splicing of MP18 (C-terminal tail: VHLISNVYGRSTSLKVVL). hnRNP K instead generates MP20 (C-terminal tail: ILSTCFLIQEFVITHHRPRL), which is inhibited both directly and indirectly by FUS. (B) TDP43 activity is regulated through three independent mechanisms. TDP43 marginal peptides (TDP-MPs) modulate flTDP43 function by (1) reducing flTDP43 synthesis—TDP43 binds TARDBP pre-mRNA to inhibit flTDP43 splicing, while simultaneously enhancing the generation of alternatively spliced isoforms, particularly MP18; (2) dominant-negative inhibition of flTDP43—TDP-MPs bind flTDP43 via the intact N terminus but cannot participate in splicing, thereby blocking the repression of cryptic exons by flTDP43; and (3) enhancing flTDP43 clearance—TDP-MPs are unstable and promote flTDP43 degradation through their physical association with flTDP43.