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01-10-2003 | Regular Paper

The L266V tau mutation is associated with frontotemporal dementia and Pick-like 3R and 4R tauopathy

Authors: Marion Hogg, Zoran M. Grujic, Matt Baker, Serpil Demirci, Angela L. Guillozet, Alison P. Sweet, Laura L. Herzog, Sandra Weintraub, M.-Marsel Mesulam, Nichole E. LaPointe, T. C. Gamblin, Robert W. Berry, Lester I. Binder, Rohan de Silva, Andrew Lees, Marisol Espinoza, Peter Davies, Andrew Grover, Naruhiko Sahara, Takashi Ishizawa, Dennis Dickson, Shu-Hui Yen, Michael Hutton, Eileen H. Bigio

Published in: Acta Neuropathologica | Issue 4/2003

Abstract

We report a case of rapidly progressive frontotemporal dementia presenting at age 33 years. At autopsy there was severe atrophy of the frontal and temporal lobes. Tau-positive Pick bodies, which ultrastructurally were composed of straight filaments, were present, accompanied by severe neuronal loss and gliosis. RD3, a tau antibody specific for the three-repeat (3R) isoforms, labeled the Pick bodies. ET3, a four-repeat (4R) isoform-specific tau antibody, did not label Pick bodies, but highlighted rare astrocytes, and threads in white matter bundles in the corpus striatum. Analysis of the tau gene revealed an L266V mutation in exon 9. Analysis of brain tissue from this case revealed elevated levels of exon 10+ tau RNA and soluble 4R tau. However, both 3R and 4R isoforms were present in sarkosyl-insoluble tau fractions with a predominance of the shortest 3R isoform. The L266V mutation is associated with decreased rate and extent of tau-induced microtubule assembly, and a 3R isoform-specific increase in tau self assembly as measured by an in vitro assay. Combined, these data indicate that L266V is a pathogenic tau mutation that is associated with Pick-like pathology. In addition, the results of the RD3 and ET3 immunostains clearly explain for the first time the presence of both 3R and 4R tau isoforms in preparations of insoluble tau from some Pick's disease cases.

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Title: The L266V tau mutation is associated with frontotemporal dementia and Pick-like 3R and 4R tauopathy
Authors: Marion Hogg
Zoran M. Grujic
Matt Baker
Serpil Demirci
Angela L. Guillozet
Alison P. Sweet
Laura L. Herzog
Sandra Weintraub
M.-Marsel Mesulam
Nichole E. LaPointe
T. C. Gamblin
Robert W. Berry
Lester I. Binder
Rohan de Silva
Andrew Lees
Marisol Espinoza
Peter Davies
Andrew Grover
Naruhiko Sahara
Takashi Ishizawa
Dennis Dickson
Shu-Hui Yen
Michael Hutton
Eileen H. Bigio
Publication date: 01-10-2003
Publisher: Springer-Verlag
Published in: Acta Neuropathologica / Issue 4/2003
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-003-0734-x

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The L266V tau mutation is associated with frontotemporal dementia and Pick-like 3R and 4R tauopathy

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