title: Novel monoclonal antibodies to normal and pathologically altered human TDP-43 proteins.
abstract: The RNA/DNA-binding protein, TDP-43, is the key component of ubiquitinated inclusions characteristic of amyotrophic lateral sclerosis (ALS) and the majority of frontotemporal lobar degeneration (FTLD-TDP) referred to collectively as TDP-43 proteinopathies. To further elucidate mechanisms of pathological TDP-43 processing and identify TDP-43 epitopes that could be useful as potential biomarkers of TDP-43 proteinopathies, we developed a panel of novel monoclonal antibodies (MAbs) directed at regions extending across the length of TDP-43. Here, we confirm previous observations that there is no or minimal accumulation of TDP-43 N-terminal domains in neocortical inclusions in human TDP-43 proteinopathy tissues and we identify a subset of these MAbs that are specific for human versus mouse TDP-43. Notably, one of these MAbs recognized an epitope that preferentially detected pathological TDP-43 inclusions with negligible reactivity for normal nuclear TDP-43 resembling anti-phospho-TDP-43 specific antibodies that only bind pathological TDP-43. Hence, we infer that this new MAb recognizes a phosphorylation independent but disease-specific pathologic conformation in abnormal TDP-43. These data suggest that the novel MAbs reported here will be useful for patient-oriented research as well as for studies of animal and cell-based models of TDP-43 proteinopathies including ALS and FTLD-TDP.
authors.forename: Linda K
authors.initials: LK
authors.lastname: Kwong
authors.forename: David J
authors.initials: DJ
authors.lastname: Irwin
authors.forename: Adam K
authors.initials: AK
authors.lastname: Walker
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Riddle
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: Center for Neurodegenerative Disease Research & Institute on Aging, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-4283, USA. vmylee@upenn.edu.
authors.forename: Virginia M Y
authors.initials: VM
authors.lastname: Lee
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal; D000918:Antibody Specificity; D001921:Brain / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D057180:Frontotemporal Dementia / Q000175:diagnosis / Q000378:metabolism*; D006801:Humans; D051379:Mice
chemical_list: D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins