title: TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions.
abstract: TAR DNA-binding protein 43 (TDP-43) is a major pathological protein of sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease (MND). Thus, TDP-43 defines a novel class of neurodegenerative diseases called TDP-43 proteinopathies. We performed ubiquitin and TDP-43 immunohistochemistry on 193 cases of familial and sporadic FTLD with or without MND. On selected cases, immunoelectron microscopy and biochemistry were performed. Clinically defined frontotemporal dementias (FTDs) included four groups: 1) familial FTD with mutations in progranulin (n = 36), valosin-containing protein (n = 5), charged multivesicular body protein 2B (n = 4), and linked to chromosome 9p (n = 7); 2) familial cases of FTD with unknown gene association (n = 29); 3) sporadic FTD (n = 72); and 4) familial and sporadic FTD with MND (n = 40). Our studies confirm that the spectrum of TDP-43 proteinopathies includes most cases of sporadic and familial FTLD-U with and without MND and expand this disease spectrum to include reported families with FTD linked to chromosome 9p but not FTD with charged multivesicular body protein 2B mutations. Thus, despite significant clinical, genetic, and neuropathological heterogeneity of FTLD-U, TDP-43 is a common pathological substrate underlying a large subset of these disorders, thereby implicating TDP-43 in novel and unifying mechanisms of FTLD pathogenesis.
authors.affiliation: MRCPath, Department of Pathology and Immunology, Washington University School of Medicine, Campus Box 8118, St Louis, MO 63110, USA. cairns@wustl.edu
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Cairns
authors.forename: Manuela
authors.initials: M
authors.lastname: Neumann
authors.forename: Eileen H
authors.initials: EH
authors.lastname: Bigio
authors.forename: Ida E
authors.initials: IE
authors.lastname: Holm
authors.forename: Dirk
authors.initials: D
authors.lastname: Troost
authors.forename: Kimmo J
authors.initials: KJ
authors.lastname: Hatanpaa
authors.forename: Chan
authors.initials: C
authors.lastname: Foong
authors.forename: Charles L
authors.initials: CL
authors.lastname: White
authors.forename: Julie A
authors.initials: JA
authors.lastname: Schneider
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kretzschmar
authors.forename: Deborah
authors.initials: D
authors.lastname: Carter
authors.forename: Lisa
authors.initials: L
authors.lastname: Taylor-Reinwald
authors.forename: Katherine
authors.initials: K
authors.lastname: Paulsmeyer
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Strider
authors.forename: Michael
authors.initials: M
authors.lastname: Gitcho
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.forename: Manjari
authors.initials: M
authors.lastname: Mishra
authors.forename: Linda K
authors.initials: LK
authors.lastname: Kwong
authors.forename: Anna
authors.initials: A
authors.lastname: Stieber
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Mark S
authors.initials: MS
authors.lastname: Forman
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: Ian R A
authors.initials: IR
authors.lastname: Mackenzie
mesh_terms: D002893:Chromosomes, Human, Pair 3; D002899:Chromosomes, Human, Pair 9; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D003704:Dementia / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D016472:Motor Neuron Disease / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D025801:Ubiquitin