Fig 5. Summary Diagram.

TDP-43 is a highly autoregulated protein due to different forms of cellular toxicity when TDP-43 protein levels are either too low (cryptic exon incorporation) or too high (aberrant exon skipping). Our study has demonstrated that these splicing deficits are linked specifically to nuclear TDP-43, whereas toxicity due to cytoplasmic TDP-43 remains to be fully elucidated. Future studies that avoid constitutive exon skipping may identify biomarkers for cytoplasmic-specific TDP-43 toxicity.