Published online before print May 18, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.070182

Accepted for publication March 30, 2007.

Article

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 III, 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, Yan Xu, Mark S. Forman^***, John Q. Trojanowski^***, Virginia M.-Y. Lee, and Ian R.A. Mackenzie

From the Departments of Neurology,* Pathology and Immunology, and Psychiatry,^|||| Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri; the Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute on Aging,*** University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; the Center for Neuropathology and Prion Research,^¶ Ludwig-Maximilians University, Munich, Germany; the Department of Pathology,^|| Cognitive Neurology and Alzheimer Disease Center,** Northwestern University Medical School, Chicago, Illinois; the Department of Pathology, Aalborg Hospital, Aalborg, Denmark; the Department of Neuropathology, Academic Medical Centre, Amsterdam, The Netherlands; the Neuropathology Laboratory, Department of Pathology, University of Texas Southwestern Medical School, Dallas, Texas; the Rush Alzheimer's Disease Center,^¶¶ Rush University Medical School, Chicago, Illinois; and the Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, British Columbia, Canada

^@ To whom correspondence should be addressed. E-mail: cairns{at}wustl.edu.

	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.

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