title: Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.
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.
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Manuela
authors.initials: M
authors.lastname: Neumann
authors.forename: Deepak M
authors.initials: DM
authors.lastname: Sampathu
authors.forename: Linda K
authors.initials: LK
authors.lastname: Kwong
authors.forename: Adam C
authors.initials: AC
authors.lastname: Truax
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Micsenyi
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Chou
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bruce
authors.forename: Theresa
authors.initials: T
authors.lastname: Schuck
authors.forename: Murray
authors.initials: M
authors.lastname: Grossman
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Clark
authors.forename: Leo F
authors.initials: LF
authors.lastname: McCluskey
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mackenzie
authors.forename: Howard
authors.initials: H
authors.lastname: Feldman
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Feiden
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kretzschmar
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000911:Antibodies, Monoclonal; D001923:Brain Chemistry; D002540:Cerebral Cortex / Q000737:chemistry / Q000473:pathology; D004268:DNA-Binding Proteins / Q000032:analysis* / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D003704:Dementia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000737:chemistry / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000737:chemistry / Q000473:pathology; D009474:Neurons / Q000737:chemistry / Q000473:pathology; D010446:Peptide Fragments / Q000737:chemistry; D010766:Phosphorylation; D013116:Spinal Cord / Q000737:chemistry* / Q000473:pathology; D025801:Ubiquitin / Q000032:analysis*
chemical_list: D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; D010446:Peptide Fragments; D025801:Ubiquitin