Figure 3.

Mechanisms of TDP-43 truncation through alternative splicing

Center: The TDP-43 primary transcript generates a conventional mRNA splicing variant that encodes full-length TDP-43 in healthy neurons. However, under unknown conditions, at least two different kind of TDP-43 alternative transcripts can translate into N- or C-terminally truncated forms.

Top: An alternative splicing event that removes most of the TARDBP exon 6 and integrates part of the 3′UTR leads to the generation of shortened TDP-43 (sTDP-43) isoforms. These splice variants lack the conventional C-terminus and acquire a distinct 18 amino acids C-terminal tail (brown rectangle). This new sequence contains a functional putative nuclear export sequence (NES) that promotes its cytosolic accumulation as well as sequestration of normal TDP-43, resulting in neurotoxicity.

Bottom: A different splicing event gives rise to a C-terminal fragment through the use of an alternative translation initiation codon at Methionine-85 (M85) of the full-length TDP-43. The resulting isoform, referred to as Met⁸⁵-TDP-35, accumulates in cytoplasm where it can sequester endogenous TDP-43 and lead to neurotoxicity.