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

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 IshizawaDennis W Dickson, Shu Hui Yen, Michael Hutton, Eileen H. Bigio

Research output: Contribution to journalArticle

72 Citations (Scopus)

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 anti-body, 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.

Original languageEnglish (US)
Pages (from-to)323-336
Number of pages14
JournalActa Neuropathologica
Volume106
Issue number4
DOIs
StatePublished - Oct 1 2003

Fingerprint

Tauopathies
Frontotemporal Dementia
Protein Isoforms
Mutation
Exons
Pick Disease of the Brain
Corpus Striatum
Gliosis
Frontal Lobe
Temporal Lobe
Microtubules
Astrocytes
Atrophy
Autopsy
RNA
Pathology
Antibodies
Brain
Genes

Keywords

  • Exon 9
  • FTDP-17
  • Pick's disease
  • Tau
  • Tauopathy

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Neuroscience(all)

Cite this

Hogg, M., Grujic, Z. M., Baker, M., Demirci, S., Guillozet, A. L., Sweet, A. P., ... Bigio, E. H. (2003). The L266V tau mutation is associated with frontotemporal dementia and Pick-like 3R and 4R tauopathy. Acta Neuropathologica, 106(4), 323-336. https://doi.org/10.1007/s00401-003-0734-x

The L266V tau mutation is associated with frontotemporal dementia and Pick-like 3R and 4R tauopathy. / Hogg, Marion; Grujic, Zoran M.; Baker, Matt; Demirci, Serpil; Guillozet, Angela L.; Sweet, Alison P.; Herzog, Laura L.; Weintraub, Sandra; Mesulam, M. Marsel; LaPointe, Nichole E.; Gamblin, T. C.; Berry, Robert W.; Binder, Lester I.; de Silva, Rohan; Lees, Andrew; Espinoza, Marisol; Davies, Peter; Grover, Andrew; Sahara, Naruhiko; Ishizawa, Takashi; Dickson, Dennis W; Yen, Shu Hui; Hutton, Michael; Bigio, Eileen H.

In: Acta Neuropathologica, Vol. 106, No. 4, 01.10.2003, p. 323-336.

Research output: Contribution to journalArticle

Hogg, M, Grujic, ZM, Baker, M, Demirci, S, Guillozet, AL, Sweet, AP, Herzog, LL, Weintraub, S, Mesulam, MM, LaPointe, NE, Gamblin, TC, Berry, RW, Binder, LI, de Silva, R, Lees, A, Espinoza, M, Davies, P, Grover, A, Sahara, N, Ishizawa, T, Dickson, DW, Yen, SH, Hutton, M & Bigio, EH 2003, 'The L266V tau mutation is associated with frontotemporal dementia and Pick-like 3R and 4R tauopathy', Acta Neuropathologica, vol. 106, no. 4, pp. 323-336. https://doi.org/10.1007/s00401-003-0734-x
Hogg, Marion ; Grujic, Zoran M. ; Baker, Matt ; Demirci, Serpil ; Guillozet, Angela L. ; Sweet, Alison P. ; Herzog, Laura L. ; Weintraub, Sandra ; Mesulam, M. Marsel ; LaPointe, Nichole E. ; Gamblin, T. C. ; Berry, Robert W. ; Binder, Lester I. ; de Silva, Rohan ; Lees, Andrew ; Espinoza, Marisol ; Davies, Peter ; Grover, Andrew ; Sahara, Naruhiko ; Ishizawa, Takashi ; Dickson, Dennis W ; Yen, Shu Hui ; Hutton, Michael ; Bigio, Eileen H. / The L266V tau mutation is associated with frontotemporal dementia and Pick-like 3R and 4R tauopathy. In: Acta Neuropathologica. 2003 ; Vol. 106, No. 4. pp. 323-336.
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AU - Guillozet, Angela L.

AU - Sweet, Alison P.

AU - Herzog, Laura L.

AU - Weintraub, Sandra

AU - Mesulam, M. Marsel

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AU - Gamblin, T. C.

AU - Berry, Robert W.

AU - Binder, Lester I.

AU - de Silva, Rohan

AU - Lees, Andrew

AU - Espinoza, Marisol

AU - Davies, Peter

AU - Grover, Andrew

AU - Sahara, Naruhiko

AU - Ishizawa, Takashi

AU - Dickson, Dennis W

AU - Yen, Shu Hui

AU - Hutton, Michael

AU - Bigio, Eileen H.

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N2 - 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 anti-body, 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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