Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis

• Published in: Science (American Association for the Advancement of Science) 2006-10, Vol.314 (5796), p.130-133
• Main Authors: Neumann, Manuela, Sampathu, Deepak M, Kwong, Linda K, Truax, Adam C, Micsenyi, Matthew C, Chou, Thomas T, Bruce, Jennifer, Schuck, Theresa, Grossman, Murray, Clark, Christopher M, McCluskey, Leo F, Miller, Bruce L, Masliah, Eliezer, Mackenzie, Ian R, Feldman, Howard, Feiden, Wolfgang, Kretzschmar, Hans A, Trojanowski, John Q, Lee, Virginia M.-Y
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Antibodies; Antibodies, Monoclonal; Biological and medical sciences; Brain Chemistry; Cerebral Cortex - chemistry; Cerebral Cortex - pathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dementia - genetics; Dementia - metabolism; Dementia - pathology; DNA-Binding Proteins - analysis; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - immunology; Fluorescent Antibody Technique; Frontotemporal lobar degeneration; Hippocampus - chemistry; Hippocampus - pathology; Humans; Immunoblotting; Medical sciences; Molecular Sequence Data; Motor Neurons - chemistry; Motor Neurons - pathology; Nervous system diseases; Neurodegenerative diseases; Neurological disorders; Neurology; Neurons; Neurons - chemistry; Neurons - pathology; Pathology; Peptide Fragments - chemistry; Phosphorylation; Proteins; Spinal cord; Spinal Cord - chemistry; Spinal Cord - pathology; Ubiquitin - analysis; Ubiquitins
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1134108

Ubiquitin-positive, tau- and α-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.