{"doi":"10.1101/2025.07.30.667669","title":"Cytoplasmic TDP-43 leads to early functional impairments without neurodegeneration in a Serotonergic Neuron-Specific <i>C. elegans</i> Model","abstract":"Abstract TDP-43 proteinopathies, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are marked by the pathological cytoplasmic accumulation of TAR DNA-binding protein 43 (TDP-43), leading to progressive neuronal dysfunction and degeneration. To investigate the early functional consequences of TDP-43 mislocalization, we generated Caenorhabditis elegans models expressing either wild-type human TDP-43 or a variant with a mutated nuclear localization signal (ΔNLS), specifically in serotonergic neurons. These neurons were chosen because i) serotonin deficits are a feature of ALS/FTD and ii) in C. elegans , they regulate well-characterized behaviors, providing a straightforward readout of neuronal function. We found that expression of either TDP-43 variant impaired serotonin-dependent behaviors—including pharyngeal pumping, egg-laying, and locomotion slowing upon food encounter—with the cytoplasmic ΔNLS form causing more severe deficits. Serotonergic neurons remained i) morphologically intact, indicating that neuronal dysfunction precedes overt neurodegeneration; and ii) partially responsive to the selective serotonin reuptake inhibitor fluoxetine, suggesting that neurotransmitter release is still partially functional. Altogether, our findings demonstrate that cytoplasmic TDP-43 disrupts neuronal signaling and behavior early in disease progression. This C. elegans model provides a genetically tractable system to dissect early mechanisms of TDP-43-mediated dysfunction and to identify therapeutic strategies targeting predegenerative stages of ALS/FTD.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":571393,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9527,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1477549,"name":"Florencia Vasallu","orcid":null,"position":1,"is_corresponding":false},{"id":921907,"name":"Diego Rayes","orcid":"0000-0002-5448-1431","position":2,"is_corresponding":false},{"id":1477150,"name":"Lionel M. Igaz","orcid":"0000-0001-9988-3242","position":3,"is_corresponding":false},{"id":1477548,"name":"Ailín Lacour","orcid":null,"position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":null,"created_at":"2026-07-19T02:57:15.755535Z","pmid":"40766632","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}