Figure 1. Truncated STMN2 RNA is generated with loss of nuclear TDP-43.

Schematic of TDP-43–regulated STMN2 splicing. When TDP-43 is present and functional, it binds to GU-rich sequences in the first intron of the STMN2 transcript and allows normal splicing of intron 1. Reduced TDP-43 binding to STMN2 RNA, from TDP-43 aggregation or depletion from the nucleus, leads to mis-splicing of STMN2 RNA, resulting in the inclusion of a novel exon encoded within intron 1 (termed exon 2a) and containing an alternative or cryptic polyadenylation site. The production of this alternative variant of STMN2, which lacks exons 2 through 5 (referred to as truncated STMN2), is at the expense of full-length STMN2, which is reduced upon TDP-43 downregulation.