A90V TDP-43 variant results in the aberrant localization of TDP-43 in vitro

Matthew J. Winton; Vivianna M. Van Deerlin; Linda K. Kwong; Wuxing Yuan; Elisabeth Mc Carty Wood; Chang En Yu; Gerard D. Schellenberg; Rosa Rademakers; Richard Caselli; Anna Karydas; John Q. Trojanowski; Bruce L. Miller; Virginia M.Y. Lee

doi:10.1016/j.febslet.2008.05.024

A90V TDP-43 variant results in the aberrant localization of TDP-43 in vitro

Matthew J. Winton, Vivianna M. Van Deerlin, Linda K. Kwong, Wuxing Yuan, Elisabeth Mc Carty Wood, Chang En Yu, Gerard D. Schellenberg, Rosa Rademakers, Richard Caselli, Anna Karydas, John Q. Trojanowski, Bruce L. Miller, Virginia M.Y. Lee

Research output: Contribution to journal › Article › peer-review

72 Scopus citations

Abstract

TAR DNA-binding protein-43 (TDP-43) is a highly conserved, ubiquitously expressed nuclear protein that was recently identified as the disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Pathogenic TDP-43 gene (TARDBP) mutations have been identified in familial ALS kindreds, and here we report a TARDBP variant (A90V) in a FTLD/ALS patient with a family history of dementia. Significantly, A90V is located between the bipartite nuclear localization signal sequence of TDP-43 and the in vitro expression of TDP-43-A90V led to its sequestration with endogenous TDP-43 as insoluble cytoplasmic aggregates. Thus, A90V may be a genetic risk factor for FTLD/ALS because it predisposes nuclear TDP-43 to redistribute to the cytoplasm and form pathological aggregates.

Original language	English (US)
Pages (from-to)	2252-2256
Number of pages	5
Journal	FEBS Letters
Volume	582
Issue number	15
DOIs	https://doi.org/10.1016/j.febslet.2008.05.024
State	Published - Jun 25 2008

Keywords

A90V
ALS
FTLD-U
TARDBP mutations
TDP-43

ASJC Scopus subject areas

Biophysics
Structural Biology
Biochemistry
Molecular Biology
Genetics
Cell Biology

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10.1016/j.febslet.2008.05.024

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@article{0becb03bef8f4acd9fd7300729cf4b8d,

title = "A90V TDP-43 variant results in the aberrant localization of TDP-43 in vitro",

abstract = "TAR DNA-binding protein-43 (TDP-43) is a highly conserved, ubiquitously expressed nuclear protein that was recently identified as the disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Pathogenic TDP-43 gene (TARDBP) mutations have been identified in familial ALS kindreds, and here we report a TARDBP variant (A90V) in a FTLD/ALS patient with a family history of dementia. Significantly, A90V is located between the bipartite nuclear localization signal sequence of TDP-43 and the in vitro expression of TDP-43-A90V led to its sequestration with endogenous TDP-43 as insoluble cytoplasmic aggregates. Thus, A90V may be a genetic risk factor for FTLD/ALS because it predisposes nuclear TDP-43 to redistribute to the cytoplasm and form pathological aggregates.",

keywords = "A90V, ALS, FTLD-U, TARDBP mutations, TDP-43",

author = "Winton, {Matthew J.} and {Van Deerlin}, {Vivianna M.} and Kwong, {Linda K.} and Wuxing Yuan and Wood, {Elisabeth Mc Carty} and Yu, {Chang En} and Schellenberg, {Gerard D.} and Rosa Rademakers and Richard Caselli and Anna Karydas and Trojanowski, {John Q.} and Miller, {Bruce L.} and Lee, {Virginia M.Y.}",

note = "Funding Information: This work was funded by grants from the National Institute of Health/National Institute on Aging (AG10124, AG17586, AG05142, AG10129, AG16574 and MH57899) and the Pacific Alzheimer Research Foundation. V.M.-Y.L. is the John H. Ware III Professor of Alzheimer{\textquoteright}s Research and J.Q.T. is the William Maul Measey-Truman G. Schnabel, Jr., M.D. Professor of Geriatric Medicine and Gerontology. The authors would like to thank the families of patients who made this research possible. ",

year = "2008",

month = jun,

day = "25",

doi = "10.1016/j.febslet.2008.05.024",

language = "English (US)",

volume = "582",

pages = "2252--2256",

journal = "FEBS Letters",

issn = "0014-5793",

publisher = "Elsevier",

number = "15",

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TY - JOUR

T1 - A90V TDP-43 variant results in the aberrant localization of TDP-43 in vitro

AU - Winton, Matthew J.

AU - Van Deerlin, Vivianna M.

AU - Kwong, Linda K.

AU - Yuan, Wuxing

AU - Wood, Elisabeth Mc Carty

AU - Yu, Chang En

AU - Schellenberg, Gerard D.

AU - Rademakers, Rosa

AU - Caselli, Richard

AU - Karydas, Anna

AU - Trojanowski, John Q.

AU - Miller, Bruce L.

AU - Lee, Virginia M.Y.

N1 - Funding Information: This work was funded by grants from the National Institute of Health/National Institute on Aging (AG10124, AG17586, AG05142, AG10129, AG16574 and MH57899) and the Pacific Alzheimer Research Foundation. V.M.-Y.L. is the John H. Ware III Professor of Alzheimer’s Research and J.Q.T. is the William Maul Measey-Truman G. Schnabel, Jr., M.D. Professor of Geriatric Medicine and Gerontology. The authors would like to thank the families of patients who made this research possible.

PY - 2008/6/25

Y1 - 2008/6/25

N2 - TAR DNA-binding protein-43 (TDP-43) is a highly conserved, ubiquitously expressed nuclear protein that was recently identified as the disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Pathogenic TDP-43 gene (TARDBP) mutations have been identified in familial ALS kindreds, and here we report a TARDBP variant (A90V) in a FTLD/ALS patient with a family history of dementia. Significantly, A90V is located between the bipartite nuclear localization signal sequence of TDP-43 and the in vitro expression of TDP-43-A90V led to its sequestration with endogenous TDP-43 as insoluble cytoplasmic aggregates. Thus, A90V may be a genetic risk factor for FTLD/ALS because it predisposes nuclear TDP-43 to redistribute to the cytoplasm and form pathological aggregates.

AB - TAR DNA-binding protein-43 (TDP-43) is a highly conserved, ubiquitously expressed nuclear protein that was recently identified as the disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Pathogenic TDP-43 gene (TARDBP) mutations have been identified in familial ALS kindreds, and here we report a TARDBP variant (A90V) in a FTLD/ALS patient with a family history of dementia. Significantly, A90V is located between the bipartite nuclear localization signal sequence of TDP-43 and the in vitro expression of TDP-43-A90V led to its sequestration with endogenous TDP-43 as insoluble cytoplasmic aggregates. Thus, A90V may be a genetic risk factor for FTLD/ALS because it predisposes nuclear TDP-43 to redistribute to the cytoplasm and form pathological aggregates.

KW - A90V

KW - ALS

KW - FTLD-U

KW - TARDBP mutations

KW - TDP-43

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DO - 10.1016/j.febslet.2008.05.024

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AN - SCOPUS:44749093657

SN - 0014-5793

VL - 582

SP - 2252

EP - 2256

JO - FEBS Letters

JF - FEBS Letters

IS - 15

ER -

A90V TDP-43 variant results in the aberrant localization of TDP-43 in vitro

Abstract

Keywords

ASJC Scopus subject areas

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