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These hallmark pathological features are associated with widespread neuronal dysfunction and progressive neurodegeneration. TDP\u201043's role as an essential RNA\/DNA\u2010binding protein in RNA metabolism and gene expression regulation is clear, but deciphering the intricate pathophysiological mechanisms underpinning TDP\u201043\u2010mediated neurodegeneration is paramount for developing effective therapies and novel diagnostic tools for early detection before frank neuronal loss occurs. The nematode\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    , with highly conserved TDP\u201043 orthologue TDP\u20101, serves as a powerful genetic model to investigate the molecular underpinnings of TDP\u201043 proteinopathies. Here, we provide a brief overview of the structural and functional characteristics of TDP\u201043 and TDP\u20101, highlighting their conserved roles in RNA metabolism, stress responses, and neurodegeneration. We then delve into the pathobiology of TDP\u201043, drawing insights from\n                    <jats:italic>C. elegans<\/jats:italic>\n                    models expressing either monogenic TDP\u201043 variants or bigenic combinations with ALS\u2010associated risk genes, and discuss how these models have advanced our understanding of the pathomechanisms of TDP\u201043 proteinopathies. By employing its simplicity and genetic manipulability, we discuss how these models have helped identify chemical and genetic suppressors of TDP\u201043\u2010induced phenotypes, including small molecules like Pimozide and the probiotic\n                    <jats:italic>Lacticaseibacillus rhamnosus<\/jats:italic>\n                    HA\u2010114, now in clinical trials. This review underscores the translational value of\n                    <jats:italic>C. elegans<\/jats:italic>\n                    in unraveling the biochemical pathways and interactions in TDP\u201043 proteinopathies that perturb cellular physiology, potentially facilitating mechanism\u2010based therapy development.\n                  <\/jats:p>","DOI":"10.1111\/febs.70239","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T10:21:49Z","timestamp":1756808509000},"page":"348-384","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["<scp>TDP<\/scp>\n                    \u201043 proteinopathies and neurodegeneration: insights from\n                    <i>Caenorhabditis elegans<\/i>\n                    models"],"prefix":"10.1111","volume":"293","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3147-8141","authenticated-orcid":false,"given":"Ghulam Jeelani","family":"Pir","sequence":"first","affiliation":[{"name":"The Neuroscience Institute, Academic Health System Hamad Medical Corporation  Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joerg","family":"Buddenkotte","sequence":"additional","affiliation":[{"name":"Translational Research Institute, Academic Health System Hamad Medical Corporation  Doha Qatar"},{"name":"Dermatology Institute, Academic Health System Hamad Medical Corporation  Doha Qatar"},{"name":"Department of Dermatology and Venereology, Rumailah Hospital Hamad Medical Corporation  Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majid Ali","family":"Alam","sequence":"additional","affiliation":[{"name":"Translational Research Institute, Academic Health System Hamad Medical Corporation  Doha Qatar"},{"name":"Dermatology Institute, Academic Health System Hamad Medical Corporation  Doha Qatar"},{"name":"Department of Dermatology and Venereology, Rumailah Hospital Hamad Medical Corporation  Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Own","sequence":"additional","affiliation":[{"name":"The Neuroscience Institute, Academic Health System Hamad Medical Corporation  Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0461-7721","authenticated-orcid":false,"given":"Randall J.","family":"Eck","sequence":"additional","affiliation":[{"name":"Geriatrics Research Education and Clinical Center (GRECC) Veterans Affairs Puget Sound Healthcare System  Seattle WA USA"},{"name":"Division of Gerontology and Geriatric Medicine, Department of Medicine University of Washington Harborview Medical Center  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2252-7634","authenticated-orcid":false,"given":"Brian C.","family":"Kraemer","sequence":"additional","affiliation":[{"name":"Geriatrics Research Education and Clinical Center (GRECC) Veterans Affairs Puget Sound Healthcare System  Seattle WA USA"},{"name":"Division of Gerontology and Geriatric Medicine, Department of Medicine University of Washington Harborview Medical Center  Seattle WA USA"},{"name":"Department of Psychiatry and Behavioral Sciences University of Washington  Seattle WA USA"},{"name":"Department of Laboratory Medicine and Pathology University of Washington  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4655-4829","authenticated-orcid":false,"given":"Eckhard","family":"Mandelkow","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE)  Bonn Germany"},{"name":"Department of Gerontopsychiatry and Neurodegenerative Diseases UKB, University of Bonn Medical School  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7090-2187","authenticated-orcid":false,"given":"Martin","family":"Steinhoff","sequence":"additional","affiliation":[{"name":"Translational Research Institute, Academic Health System Hamad Medical Corporation  Doha Qatar"},{"name":"Dermatology Institute, Academic Health System Hamad Medical Corporation  Doha Qatar"},{"name":"Department of Dermatology and Venereology, Rumailah Hospital Hamad Medical Corporation  Doha Qatar"},{"name":"Department of Medicine Weill Cornell Medicine Qatar, Qatar Foundation\u2010Education City  Doha Qatar"},{"name":"College of Medicine Qatar University  Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,2]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0888-7543(03)00214-3"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.69.6.3584-3596.1995"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M705811200"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0800546105"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.7.1774"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M104236200"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2006.01.052"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-009-5069-7"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-008-0460-5"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/WAD.0b013e31815c3486"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1134108"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2006.10.093"},{"issue":"3","key":"e_1_2_9_14_1","first-page":"1363","article-title":"Amyotrophic 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