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

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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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Acknowledgments

We are grateful to patients and their families for the interest and generous participation in our research endeavors. We gratefully acknowledge the excellent technical assistance of Venka Subramani. This work was supported in part by NIH grants AG13854 (Z.M.G., S.D., A.L.G., A.P.S., L.L.H., S.W., M.M.M., and E.H.B.) and AG14453 (L.I.B.), NIA program grant PO1 AG17216 (M.H., D.D., and S.-H.Y.), and the Mayo foundation.

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Authors and Affiliations

  1. Neurogenetics Laboratory, Mayo Clinic Jacksonville, Jacksonville, Florida, USA

    Marion Hogg, Matt Baker, Andrew Grover, Naruhiko Sahara, Takashi Ishizawa, Dennis Dickson, Shu-Hui Yen & Michael Hutton

  2. Department of Neurology, Evanston Northwestern Healthcare, Evanston, Illinois, USA

    Zoran M. Grujic

  3. Northwestern Cognitive Neurology and Alzheimer Disease Center, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA

    Serpil Demirci, Angela L. Guillozet, Alison P. Sweet, Laura L. Herzog, Sandra Weintraub, M.-Marsel Mesulam, Robert W. Berry, Lester I. Binder & Eileen H. Bigio

  4. Department of Pathology, Northwestern University, Feinberg School of Medicine, 710 N. Fairbanks Ct., Olson 3-459, Chicago, IL, 60611, USA

    Alison P. Sweet & Eileen H. Bigio

  5. Department of Psychiatry and Behavioral Science, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA

    Sandra Weintraub

  6. Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA

    M.-Marsel Mesulam

  7. Department of Cell and Molecular Biology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA

    Nichole E. LaPointe, T. C. Gamblin, Robert W. Berry & Lester I. Binder

  8. Reta Lila Weston Institute of Neurological Studies, Royal Free and University College Medical School, London, UK

    Rohan de Silva & Andrew Lees

  9. Albert Einstein College of Medicine, Bronx, NY, USA

    Marisol Espinoza & Peter Davies

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  1. Marion Hogg
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  2. Zoran M. Grujic
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Correspondence to Eileen H. Bigio.

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Hogg, M., Grujic, Z.M., Baker, M. et al. The L266V tau mutation is associated with frontotemporal dementia and Pick-like 3R and 4R tauopathy. Acta Neuropathol 106, 323–336 (2003). https://doi.org/10.1007/s00401-003-0734-x

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