TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions

Nigel J. Cairns, Manuela Neumann, Eileen H. Bigio, Ida E. Holm, Dirk Troost, Kimmo J. Hatanpaa, Chan Foong, Charles L. White, Julie A. Schneider, Hans A. Kretzschmar, Deborah Carter, Lisa Taylor-Reinwald, Katherine Paulsmeyer, Jeffrey Strider, Michael Gitcho, Alison M. Goate, John C. Morris, Manjari Mishra, Linda K. Kwong, Anna Stieber & 5 others Yan Xu, Mark S. Forman, John Q. Trojanowski, Virginia M Y Lee, Ian R A Mackenzie

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Abstract

TAR DNA-buiding 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.

Original languageEnglish (US)
Pages (from-to)227-240
Number of pages14
JournalAmerican Journal of Pathology
Volume171
Issue number1
DOIs
StatePublished - Jul 2007

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Frontotemporal Lobar Degeneration
Ubiquitin
Frontotemporal Dementia
DNA
Proteins
Motor Neuron Disease
Multivesicular Bodies
Chromosomes
Mutation
Genetic Heterogeneity
Immunoelectron Microscopy
Neurodegenerative Diseases
Biochemistry
Dementia
Immunohistochemistry

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Cairns, N. J., Neumann, M., Bigio, E. H., Holm, I. E., Troost, D., Hatanpaa, K. J., ... Mackenzie, I. R. A. (2007). TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. American Journal of Pathology, 171(1), 227-240. https://doi.org/10.2353/ajpath.2007.070182

TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. / Cairns, Nigel J.; Neumann, Manuela; Bigio, Eileen H.; Holm, Ida E.; Troost, Dirk; Hatanpaa, Kimmo J.; Foong, Chan; White, Charles L.; Schneider, Julie A.; Kretzschmar, Hans A.; Carter, Deborah; Taylor-Reinwald, Lisa; Paulsmeyer, Katherine; Strider, Jeffrey; Gitcho, Michael; Goate, Alison M.; Morris, John C.; Mishra, Manjari; Kwong, Linda K.; Stieber, Anna; Xu, Yan; Forman, Mark S.; Trojanowski, John Q.; Lee, Virginia M Y; Mackenzie, Ian R A.

In: American Journal of Pathology, Vol. 171, No. 1, 07.2007, p. 227-240.

Research output: Contribution to journalArticle

Cairns, NJ, Neumann, M, Bigio, EH, Holm, IE, Troost, D, Hatanpaa, KJ, Foong, C, White, CL, Schneider, JA, Kretzschmar, HA, Carter, D, Taylor-Reinwald, L, Paulsmeyer, K, Strider, J, Gitcho, M, Goate, AM, Morris, JC, Mishra, M, Kwong, LK, Stieber, A, Xu, Y, Forman, MS, Trojanowski, JQ, Lee, VMY & Mackenzie, IRA 2007, 'TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions', American Journal of Pathology, vol. 171, no. 1, pp. 227-240. https://doi.org/10.2353/ajpath.2007.070182
Cairns, Nigel J. ; Neumann, Manuela ; Bigio, Eileen H. ; Holm, Ida E. ; Troost, Dirk ; Hatanpaa, Kimmo J. ; Foong, Chan ; White, Charles L. ; Schneider, Julie A. ; Kretzschmar, Hans A. ; Carter, Deborah ; Taylor-Reinwald, Lisa ; Paulsmeyer, Katherine ; Strider, Jeffrey ; Gitcho, Michael ; Goate, Alison M. ; Morris, John C. ; Mishra, Manjari ; Kwong, Linda K. ; Stieber, Anna ; Xu, Yan ; Forman, Mark S. ; Trojanowski, John Q. ; Lee, Virginia M Y ; Mackenzie, Ian R A. / TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. In: American Journal of Pathology. 2007 ; Vol. 171, No. 1. pp. 227-240.
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AU - Cairns, Nigel J.

AU - Neumann, Manuela

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AU - Troost, Dirk

AU - Hatanpaa, Kimmo J.

AU - Foong, Chan

AU - White, Charles L.

AU - Schneider, Julie A.

AU - Kretzschmar, Hans A.

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AU - Paulsmeyer, Katherine

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AU - Gitcho, Michael

AU - Goate, Alison M.

AU - Morris, John C.

AU - Mishra, Manjari

AU - Kwong, Linda K.

AU - Stieber, Anna

AU - Xu, Yan

AU - Forman, Mark S.

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AU - Mackenzie, Ian R A

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N2 - TAR DNA-buiding 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.

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