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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Amyloid / chemistry*
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Amyloid / immunology
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Animals
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Antibodies, Monoclonal / biosynthesis
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Antibodies, Monoclonal / chemistry
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Cell Line, Tumor
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Cerebral Cortex / chemistry
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Cerebral Cortex / immunology
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Cerebral Cortex / pathology*
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DNA-Binding Proteins / chemistry*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / immunology
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Embryo, Mammalian
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Epitopes / chemistry
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Epitopes / immunology
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Escherichia coli / genetics
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Escherichia coli / metabolism
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Frontotemporal Dementia / genetics
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Frontotemporal Dementia / immunology
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Frontotemporal Dementia / pathology*
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Gene Expression
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HEK293 Cells
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Humans
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Injections, Intraventricular
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Male
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Mice
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Molecular Sequence Data
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Neurons / chemistry
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Neurons / immunology
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Neurons / pathology
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Primary Cell Culture
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Protein Aggregates
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Protein Aggregation, Pathological / genetics
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Protein Aggregation, Pathological / immunology
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Protein Aggregation, Pathological / pathology*
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / immunology
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TDP-43 Proteinopathies / genetics
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TDP-43 Proteinopathies / immunology
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TDP-43 Proteinopathies / pathology*
Substances
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Amyloid
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Antibodies, Monoclonal
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DNA-Binding Proteins
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Epitopes
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Protein Aggregates
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Recombinant Fusion Proteins
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TARDBP protein, human