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

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• 作者：Matthew J. Winton ; Vivianna M. Van Deerlin ; Linda K. Kwong ; Wuxing Yuan ; Elisabeth McCarty Wood ; Chang-En Yu ; Gerard D. Schellenberg ; Rosa Rademakers ; Richard Caselli ; Anna Karydas ; John Q. Trojanowsk
• 关键词：TDP-43 ; FTLD-U ; ALS ; TARDBP mutations ; A90V
• 刊名：FEBS Letters
• 出版年：2008
• 期刊代码：70_00145793
• 类别：bio
• 出版时间：25 June 2008
• 卷：582
• 期：15
• 页码：2252-2256
• 文件大小：342 K

摘要

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.