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 journalArticlepeer-review

72 Scopus citations


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
Issue number15
StatePublished - Jun 25 2008


  • 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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