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

While predominantly nuclear localized in healthy cells, TDP-43 can transit between the nucleus and cytoplasm. In frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS), TDP-43 accumulates in hyperphosphorylated cytoplasmic aggregates. However, a subset of patients develops nuclear aggregates. Expression of wild-type TDP-43 in C. elegans neurons results in nuclear protein accumulation and toxic gain of function. 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 cause less neuronal dysfunction in C. elegans. Using RNA sequencing, we determine that transcriptomes are largely unchanged in these models. However, we identify innate immune pathway increases in response to cytoplasmic but not nuclear TDP-43. We find phosphorylation-mediated neurotoxicity of both cytoplasmic and nuclear localized TDP-43 is controlled by the phosphatase calcineurin. We also find that overexpression of the unfolded protein response (UPR) transcription factor XBP-1s worsens outcomes for wild-type TDP-43 animals but improves TDP-43 ΔNLS, suggesting different pathways controlling toxicity and clearance of nuclear versus cytoplasmic TDP-43. Taken together, these data support shared and distinct cellular responses to nuclear versus cytoplasmic TDP-43 localization in an intact animal nervous system. This comparative approach supports a better understanding of human disease and informs therapeutic development for pathological subtypes of TDP-43 proteinopathies.