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 McCarty Wood, Chang En Yu, Gerard D. Schellenberg, Rosa V Rademakers, Richard John Caselli, Anna Karydas, John Q. Trojanowski, Bruce L. Miller, Virginia M Y Lee

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)2252-2256
Number of pages5
JournalFEBS Letters
Volume582
Issue number15
DOIs
StatePublished - Jun 25 2008

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DNA-Binding Proteins
Amyotrophic Lateral Sclerosis
Frontotemporal Lobar Degeneration
Frontotemporal Dementia
Nuclear Localization Signals
Nuclear Proteins
Protein Sorting Signals
Ubiquitin
Dementia
In Vitro Techniques
Cytoplasm
Genes
Mutation
Proteins

Keywords

  • A90V
  • ALS
  • FTLD-U
  • TARDBP mutations
  • TDP-43

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Winton, M. J., Van Deerlin, V. M., Kwong, L. K., Yuan, W., Wood, E. M., Yu, C. E., ... Lee, V. M. Y. (2008). A90V TDP-43 variant results in the aberrant localization of TDP-43 in vitro. FEBS Letters, 582(15), 2252-2256. https://doi.org/10.1016/j.febslet.2008.05.024

A90V TDP-43 variant results in the aberrant localization of TDP-43 in vitro. / Winton, Matthew J.; Van Deerlin, Vivianna M.; Kwong, Linda K.; Yuan, Wuxing; Wood, Elisabeth McCarty; Yu, Chang En; Schellenberg, Gerard D.; Rademakers, Rosa V; Caselli, Richard John; Karydas, Anna; Trojanowski, John Q.; Miller, Bruce L.; Lee, Virginia M Y.

In: FEBS Letters, Vol. 582, No. 15, 25.06.2008, p. 2252-2256.

Research output: Contribution to journalArticle

Winton, MJ, Van Deerlin, VM, Kwong, LK, Yuan, W, Wood, EM, Yu, CE, Schellenberg, GD, Rademakers, RV, Caselli, RJ, Karydas, A, Trojanowski, JQ, Miller, BL & Lee, VMY 2008, 'A90V TDP-43 variant results in the aberrant localization of TDP-43 in vitro', FEBS Letters, vol. 582, no. 15, pp. 2252-2256. https://doi.org/10.1016/j.febslet.2008.05.024
Winton MJ, Van Deerlin VM, Kwong LK, Yuan W, Wood EM, Yu CE et al. A90V TDP-43 variant results in the aberrant localization of TDP-43 in vitro. FEBS Letters. 2008 Jun 25;582(15):2252-2256. https://doi.org/10.1016/j.febslet.2008.05.024
Winton, Matthew J. ; Van Deerlin, Vivianna M. ; Kwong, Linda K. ; Yuan, Wuxing ; Wood, Elisabeth McCarty ; Yu, Chang En ; Schellenberg, Gerard D. ; Rademakers, Rosa V ; Caselli, Richard John ; Karydas, Anna ; Trojanowski, John Q. ; Miller, Bruce L. ; Lee, Virginia M Y. / A90V TDP-43 variant results in the aberrant localization of TDP-43 in vitro. In: FEBS Letters. 2008 ; Vol. 582, No. 15. pp. 2252-2256.
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