TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions.
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.
Cairns
Nigel J
NJ
MRCPath, Department of Pathology and Immunology, Washington University School of Medicine, Campus Box 8118, St Louis, MO 63110, USA. cairns@wustl.edu
Neumann
Manuela
M
Bigio
Eileen H
EH
Holm
Ida E
IE
Troost
Dirk
D
Hatanpaa
Kimmo J
KJ
Foong
Chan
C
White
Charles L
CL
Schneider
Julie A
JA
Kretzschmar
Hans A
HA
Carter
Deborah
D
Taylor-Reinwald
Lisa
L
Paulsmeyer
Katherine
K
Strider
Jeffrey
J
Gitcho
Michael
M
Goate
Alison M
AM
Morris
John C
JC
Mishra
Manjari
M
Kwong
Linda K
LK
Stieber
Anna
A
Xu
Yan
Y
Forman
Mark S
MS
Trojanowski
John Q
JQ
Lee
Virginia M-Y
VM
Mackenzie
Ian R A
IR
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*
D004268:DNA-Binding Proteins; D025801:Ubiquitin