Abstract
Ubiquitin-positive, tau- and alpha-synuclein-negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders.
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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Amyotrophic Lateral Sclerosis / metabolism*
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Amyotrophic Lateral Sclerosis / pathology
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Antibodies, Monoclonal
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Brain Chemistry*
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Cerebral Cortex / chemistry
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Cerebral Cortex / pathology
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DNA-Binding Proteins / analysis*
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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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Dementia / genetics
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Dementia / metabolism*
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Dementia / pathology
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Fluorescent Antibody Technique
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Hippocampus / chemistry
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Hippocampus / pathology
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Humans
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Immunoblotting
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Molecular Sequence Data
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Motor Neurons / chemistry
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Motor Neurons / pathology
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Neurons / chemistry
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Neurons / pathology
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Peptide Fragments / chemistry
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Phosphorylation
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Spinal Cord / chemistry*
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Spinal Cord / pathology
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Ubiquitin / analysis*
Substances
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Antibodies, Monoclonal
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DNA-Binding Proteins
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Peptide Fragments
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Ubiquitin