{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE326nnn/GSE326885/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Caenorhabditis elegans"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE326885"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Shared and distinct gain-of-function consequences from pathologic cytoplasmic versus nuclear TDP-43","description":"While predominantly nuclear localized in healthy cells, TDP-43 can transport 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 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. Using RNA sequencing, we found innate immune pathway increases in response to cytoplasmic but not nuclear TDP-43. We also found that overexpression of the unfolded protein response (UPR) transcription factor XBP-1s worsened outcomes for wild-type TDP-43 animals but improved TDP-43deltaNLS, suggesting different pathways controlling toxicity and clearance of nuclear versus cytoplasmic TDP-43. Taken together, this comparative approach supports a better understanding of human disease by allowing the study of cytoplasmic TDP-43 alongside nuclear TDP-43 models.","dates":{"publication":"2026/08/05"},"accession":"GSE326885","cross_references":{"GSM":["GSM9642067","GSM9642066","GSM9642069","GSM9642068","GSM9642063","GSM9642073","GSM9642062","GSM9642065","GSM9642064","GSM9642070","GSM9642072","GSM9642071"],"GPL":["34620"],"GSE":["326885"],"taxon":["Caenorhabditis elegans"]}}