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 Ishizawa; Dennis Dickson; Shu Hui Yen; Michael Hutton; Eileen H. Bigio

doi:10.1007/s00401-003-0734-x

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 Dickson, Shu Hui Yen, Michael Hutton, Eileen H. Bigio^*

^*Corresponding author for this work

Research output: Contribution to journal › Review article › peer-review

87 Scopus citations

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 language	English (US)
Pages (from-to)	323-336
Number of pages	14
Journal	Acta Neuropathologica
Volume	106
Issue number	4
DOIs	https://doi.org/10.1007/s00401-003-0734-x
State	Published - Oct 1 2003

Funding

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.

Keywords

Exon 9
FTDP-17
Pick's disease
Tau
Tauopathy

ASJC Scopus subject areas

Clinical Neurology
Cellular and Molecular Neuroscience
Pathology and Forensic Medicine

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10.1007/s00401-003-0734-x

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Hogg, M., Grujic, Z. M., Baker, M., Demirci, S., Guillozet, A. L., Sweet, A. P., Herzog, L. L., Weintraub, S., Mesulam, M. M., LaPointe, N. E., Gamblin, T. C., Berry, R. W., Binder, L. I., de Silva, R., Lees, A., Espinoza, M., Davies, P., Grover, A., Sahara, N., ... 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

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

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.",

keywords = "Exon 9, FTDP-17, Pick's disease, Tau, Tauopathy",

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

note = "Funding Information: 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.",

year = "2003",

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doi = "10.1007/s00401-003-0734-x",

language = "English (US)",

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pages = "323--336",

journal = "Acta Neuropathologica",

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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, D, 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

TY - JOUR

T1 - The L266V tau mutation is associated with frontotemporal dementia and Pick-like 3R and 4R tauopathy

AU - Hogg, Marion

AU - Grujic, Zoran M.

AU - Baker, Matt

AU - Demirci, Serpil

AU - Guillozet, Angela L.

AU - Sweet, Alison P.

AU - Herzog, Laura L.

AU - Weintraub, Sandra

AU - Mesulam, M. Marsel

AU - LaPointe, Nichole E.

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

AU - Yen, Shu Hui

AU - Hutton, Michael

AU - Bigio, Eileen H.

N1 - Funding Information: 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.

PY - 2003/10/1

Y1 - 2003/10/1

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.

AB - 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.

KW - Exon 9

KW - FTDP-17

KW - Pick's disease

KW - Tau

KW - Tauopathy

UR - http://www.scopus.com/inward/record.url?scp=0142062488&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0142062488&partnerID=8YFLogxK

U2 - 10.1007/s00401-003-0734-x

DO - 10.1007/s00401-003-0734-x

M3 - Review article

C2 - 12883828

AN - SCOPUS:0142062488

SN - 0001-6322

VL - 106

SP - 323

EP - 336

JO - Acta Neuropathologica

JF - Acta Neuropathologica

IS - 4

ER -

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

Abstract

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