Shared and distinct gain-of-function consequences from pathologic cytoplasmic versus nuclear TDP-43

In frontotemporal lobar degeneration (FTLD-TDP) and Amyotrophic Lateral Sclerosis (ALS), TDP-43 accumulates in hyperphosphorylated cytoplasmic aggregates. However, a subset of patients develop nuclear aggregates.

Expression of wild-type TDP-43 in C. elegans neurons results in nuclear protein accumulation and gain of function neuronal dysfunction. To enable comparative study of nuclear and cytoplasmic TDP-43 phenotypes, we generated new models with inactivating mutations in the nuclear localization sequence (NLS) of TDP-43. When compared to nuclear TDP-43 strains, similar protein levels of cytoplasmic TDP-43 caused less neuronal dysfunction in C. elegans.