Figure 1.

Regulatory mechanisms involved in maintaining cellular TDP-43. The production of TDP-43 is under strict autoregulation where nuclear TDP-43 protein binds to the 3′UTR of its transcript and triggers alternative splicing which leads to nonsense-mediated decay. Cytoplasmic TDP-43 may form ubiquitinated phosphorylated aggregates when the protein concentration is elevated or when the cells are stressed. These aggregates can be resolved by chaperone proteins HSP70 and DNAJB2, or can be degraded via autophagy or CMA. Soluble cytoplasmic TDP-43 is largely degraded via the UPS. The figure was created with BioRender.com.