Fig. 1.

Inclusion of an in-frame cryptic exon within a mature RNA transcript can generate de novo cryptic peptides, such as HDGFL2-CE. (A) In response to TDP-43 nuclear depletion, transcripts can be misspliced to include a cryptic exon, disrupting the transcript and resulting in its degradation either at the RNA or protein level. Therefore, these targets are not viable for biomarkers. (B) In some cases, the cryptic exon can be incorporated in-frame, yielding a cryptic peptide, such as in HDGFL2, where a cryptic exon is incorporated in-frame between exons 5 and 6 in the mature transcript.