Winton Matthew J, Van Deerlin Vivianna M, Kwong Linda K, Yuan Wuxing, Wood Elisabeth McCarty, Yu Chang-En, Schellenberg Gerard D, Rademakers Rosa, Caselli Richard, Karydas Anna, Trojanowski John Q, Miller Bruce L, Lee Virginia M-Y
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
FEBS Lett. 2008 Jun 25;582(15):2252-6. doi: 10.1016/j.febslet.2008.05.024. Epub 2008 May 27.
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.
TAR DNA结合蛋白43（TDP - 43）是一种高度保守、广泛表达的核蛋白，最近被确定为伴有泛素阳性包涵体的额颞叶痴呆（FTLD - U）和肌萎缩侧索硬化症（ALS）中的疾病相关蛋白。在家族性ALS家系中已鉴定出致病性TDP - 43基因（TARDBP）突变，在此我们报告一名有痴呆家族史的FTLD/ALS患者中存在TARDBP变体（A90V）。重要的是，A90V位于TDP - 43的双分型核定位信号序列之间，并且TDP - 43 - A90V的体外表达导致其与内源性TDP - 43一起被隔离为不溶性细胞质聚集体。因此，A90V可能是FTLD/ALS的遗传危险因素，因为它使核TDP - 43易重新分布到细胞质并形成病理性聚集体。
