{"doi":"10.1111/febs.70239","title":"<scp>TDP</scp> ‐43 proteinopathies and neurodegeneration: insights from <i>Caenorhabditis elegans</i> models","abstract":"TDP-linked proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE), are characterised by pathogenic deposits containing transactive response DNA-binding protein 43 (TDP-43) in the brain and spinal cord of patients. These hallmark pathological features are associated with widespread neuronal dysfunction and progressive neurodegeneration. TDP-43's role as an essential RNA/DNA-binding protein in RNA metabolism and gene expression regulation is clear, but deciphering the intricate pathophysiological mechanisms underpinning TDP-43-mediated neurodegeneration is paramount for developing effective therapies and novel diagnostic tools for early detection before frank neuronal loss occurs. The nematode Caenorhabditis elegans, with highly conserved TDP-43 orthologue TDP-1, serves as a powerful genetic model to investigate the molecular underpinnings of TDP-43 proteinopathies. Here, we provide a brief overview of the structural and functional characteristics of TDP-43 and TDP-1, highlighting their conserved roles in RNA metabolism, stress responses, and neurodegeneration. We then delve into the pathobiology of TDP-43, drawing insights from C. elegans models expressing either monogenic TDP-43 variants or bigenic combinations with ALS-associated risk genes, and discuss how these models have advanced our understanding of the pathomechanisms of TDP-43 proteinopathies. By employing its simplicity and genetic manipulability, we discuss how these models have helped identify chemical and genetic suppressors of TDP-43-induced phenotypes, including small molecules like Pimozide and the probiotic Lacticaseibacillus rhamnosus HA-114, now in clinical trials. This review underscores the translational value of C. elegans in unraveling the biochemical pathways and interactions in TDP-43 proteinopathies that perturb cellular physiology, potentially facilitating mechanism-based therapy development.","journal":"FEBS Journal","year":2025,"id":546578,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9575,"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":1438239,"name":"Joerg Buddenkotte","orcid":"0000-0002-2394-3269","position":1,"is_corresponding":false},{"id":1438240,"name":"Majid Alam","orcid":"0000-0002-5783-6605","position":2,"is_corresponding":false},{"id":1438677,"name":"Ahmed Own","orcid":null,"position":3,"is_corresponding":false},{"id":392264,"name":"Randall J. Eck","orcid":"0000-0003-0461-7721","position":4,"is_corresponding":false},{"id":351412,"name":"Brian C. Kraemer","orcid":"0000-0002-2252-7634","position":5,"is_corresponding":false},{"id":326010,"name":"Eckhard Mandelkow�","orcid":"0000-0003-4655-4829","position":6,"is_corresponding":false},{"id":857931,"name":"Martin Steinhoff","orcid":"0000-0002-7090-2187","position":7,"is_corresponding":false},{"id":1438238,"name":"Ghulam Jeelani Pir","orcid":"0000-0002-3147-8141","position":0,"is_corresponding":true}],"reference_count":320,"raw_metadata":null,"created_at":"2026-07-19T02:53:32.285899Z","pmid":"40891506","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":[]}