biostudies-literatureZheng XFundamental Research Funds for the Central UniversitiesNatural Science Foundation of Shaanxi ProvinceNational Natural Science Foundation of ChinaKey Research and Development Plan of Shaanxi ProvinceNatural Science Foundation655-669https://www.ebi.ac.uk/biostudies/studies/S-EPMC11258413biostudies-literatureUnknown83(8)The RNA/DNA-binding protein TDP-43 plays a pivotal role in the ubiquitinated inclusions characteristic of TDP-43 proteinopathies, including most cases of frontotemporal lobar degeneration (FTLD-TDP) and Alzheimer disease (AD). To understand the mechanisms of pathological TDP-43 processing and identify potential biomarkers, we generated novel phosphorylation-independent monoclonal antibodies (MAbs) using bacteria-expressed human full-length recombinant TDP-43. Remarkably, we identified a distinctive MAb, No. 9, targeting an epitope in amino acid (aa) region 311-360 of the C-terminus. This antibody showed preferential reactivity for pathological TDP-43 inclusions, with only mild reactivity for normal nuclear TDP-43. MAb No. 9 revealed more pathology in FTLD-TDP type A and type B brains and iJournal of neuropathology and experimental neurologyProduction and characterization of novel monoclonal antibodies against pathological human TDP-43 proteins.PMC112584132023-JC-YB-642GK2021070182018SF-10681773265GK202007023Wang MSimayi DXia HZheng XMao QMa XYang PHe QChen SSun XZhao JfalseProduction and characterization of novel monoclonal antibodies against pathological human TDP-43 proteins.The RNA/DNA-binding protein TDP-43 plays a pivotal role in the ubiquitinated inclusions characteristic of TDP-43 proteinopathies, including most cases of frontotemporal lobar degeneration (FTLD-TDP) and Alzheimer disease (AD). To understand the mechanisms of pathological TDP-43 processing and identify potential biomarkers, we generated novel phosphorylation-independent monoclonal antibodies (MAbs) using bacteria-expressed human full-length recombinant TDP-43. Remarkably, we identified a distinctive MAb, No. 9, targeting an epitope in amino acid (aa) region 311-360 of the C-terminus. This antibody showed preferential reactivity for pathological TDP-43 inclusions, with only mild reactivity for normal nuclear TDP-43. MAb No. 9 revealed more pathology in FTLD-TDP type A and type B brains and i2024-01-01T00:00:00Z2024 Aug2025-04-26T22:18:18.993Z2025-04-06T17:12:27.765ZS-EPMC112584133872800910.1093/jnen/nlae042