title: Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients.
abstract: Proteinaceous inclusions are common hallmarks of many neurodegenerative diseases. TDP-43 proteinopathies, consisting of several neurodegenerative diseases, including frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS), are characterized by inclusion bodies formed by polyubiquitinated and hyperphosphorylated full-length and truncated TDP-43. The structural properties of TDP-43 aggregates and their relationship to pathogenesis are still ambiguous. Here we demonstrate that the recombinant full-length human TDP-43 forms structurally stable, spherical oligomers that share common epitopes with an anti-amyloid oligomer-specific antibody. The TDP-43 oligomers are stable, have exposed hydrophobic surfaces, exhibit reduced DNA binding capability and are neurotoxic in vitro and in vivo. Moreover, TDP-43 oligomers are capable of cross-seeding Alzheimer's amyloid-β to form amyloid oligomers, demonstrating interconvertibility between the amyloid species. Such oligomers are present in the forebrain of transgenic TDP-43 mice and FTLD-TDP patients. Our results suggest that aside from filamentous aggregates, TDP-43 oligomers may play a role in TDP-43 pathogenesis.
authors.affiliation: 1] Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang District, Taipei 115, Taiwan [2] Institute of Bioinformatics and Structural Biology, National Tsing Hua University, 101, Kuang fu Road, Section 2, Hsinchu 30013, Taiwan.
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Fang
authors.affiliation: 1] Institute of Clinical Medicine, National Cheng Kung University, 1, University Road, Tainan 701, Taiwan [2] Institute of Basic Medical Science, National Cheng Kung University, 1, University Road, Tainan 701, Taiwan.
authors.forename: Kuen-Jer
authors.initials: KJ
authors.lastname: Tsai
authors.affiliation: Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang District, Taipei 115, Taiwan.
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Chang
authors.affiliation: Department of Pathology and Laboratory Medicine, Alzheimer's Disease Center, University of California Davis Medical Center, 2805 50th Street, Sacramento, California 95817, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Kao
authors.affiliation: Department of Pathology and Laboratory Medicine, Alzheimer's Disease Center, University of California Davis Medical Center, 2805 50th Street, Sacramento, California 95817, USA.
authors.forename: Rima
authors.initials: R
authors.lastname: Woods
authors.affiliation: Institute of Molecular Biology, Academia Sinica, 128, Academia Road, Section 2, Nankang District, Taipei 115, Taiwan.
authors.forename: Pan-Hsien
authors.initials: PH
authors.lastname: Kuo
authors.affiliation: 1] Institute of Clinical Medicine, National Cheng Kung University, 1, University Road, Tainan 701, Taiwan [2] Institute of Basic Medical Science, National Cheng Kung University, 1, University Road, Tainan 701, Taiwan.
authors.forename: Cheng-Chun
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Institute of Brain Science, School of Medicine, National Yang Ming University, 155, Linong Street, Section 2, Taipei 112, Taiwan.
authors.forename: Jhih-Ying
authors.initials: JY
authors.lastname: Liao
authors.affiliation: 1] Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang District, Taipei 115, Taiwan [2] Institute of Microbiology and Immunology, School of Life Sciences, National Yang Ming University, 155, Linong Street, Section 2, Taipei 112, Taiwan.
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Chou
authors.affiliation: Department of Chemistry, National Taiwan University, 1, Roosevelt Road, Section 4, Taipei 106, Taiwan.
authors.forename: Vinson
authors.initials: V
authors.lastname: Lin
authors.affiliation: Department of Pathology and Laboratory Medicine, Alzheimer's Disease Center, University of California Davis Medical Center, 2805 50th Street, Sacramento, California 95817, USA.
authors.forename: Lee-Way
authors.initials: LW
authors.lastname: Jin
authors.affiliation: Institute of Molecular Biology, Academia Sinica, 128, Academia Road, Section 2, Nankang District, Taipei 115, Taiwan.
authors.forename: Hanna S
authors.initials: HS
authors.lastname: Yuan
authors.affiliation: Institute of Brain Science, School of Medicine, National Yang Ming University, 155, Linong Street, Section 2, Taipei 112, Taiwan.
authors.forename: Irene H
authors.initials: IH
authors.lastname: Cheng
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, 128, Academia Road, Section 2, Nankang District, Taipei 115, Taiwan.
authors.forename: Pang-Hsien
authors.initials: PH
authors.lastname: Tu
authors.affiliation: 1] Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang District, Taipei 115, Taiwan [2] Institute of Bioinformatics and Structural Biology, National Tsing Hua University, 101, Kuang fu Road, Section 2, Hsinchu 30013, Taiwan.
authors.forename: Yun-Ru
authors.initials: YR
authors.lastname: Chen
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000737:chemistry; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000737:chemistry / Q000276:immunology / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D004622:Embryo, Mammalian; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D057180:Frontotemporal Dementia / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D061251:Primary Cell Culture; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D057177:TDP-43 Proteinopathies / Q000235:genetics / Q000276:immunology / Q000473:pathology*
chemical_list: D000682:Amyloid; D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; D000939:Epitopes; D066329:Protein Aggregates; D011993:Recombinant Fusion Proteins; C000598624:TARDBP protein, human