Robertson Janice, Sanelli Teresa, Xiao Shangxi, Yang Wencheng, Horne Patrick, Hammond Robert, Pioro Erik P, Strong Michael J
Centre for Research in Neurodegenerative Diseases, Department of Laboratory, Medicine and Pathobiology, University of Toronto, Toronto, Canada M5S 3H2.
Neurosci Lett. 2007 Jun 13;420(2):128-32. doi: 10.1016/j.neulet.2007.03.066. Epub 2007 Apr 8.
Mislocalization of the TAR-DNA binding protein (TDP-43) from the nucleus to the cytoplasm of diseased motor neurons and association with intraneuronal ubiquitinated inclusions has recently been reported in amyotrophic lateral sclerosis (ALS). Here, we have investigated TDP-43 immunoreactivity in three lines of mutant SOD1 transgenic mice, G93A, G37R and G85R and compared with labeling in one sporadic ALS case and two familial ALS cases carrying mutations in SOD1, A4T and I113T. Our findings show that there is no mislocalization of TDP-43 to the cytoplasm in motor neurons of mutant SOD1 transgenic mice, nor association of TDP-43 with ubiquitinated inclusions. In contrast, mislocalization of TDP-43 to the cytoplasm and association with ubiquitinated inclusions was found in the ALS cases, including those carrying mutations in SOD1. Interestingly, there was no association of TDP-43 with ubiquitinated hyaline conglomerate inclusions, pathology closely associated with ALS cases carrying mutations in SOD1. Our findings indicate that the process of motor neuron degeneration in mutant SOD1 transgenic mice is unlikely to involve the abnormalities of TDP-43 described in the human disease.
近期有报道称，在肌萎缩侧索硬化症（ALS）中，TAR-DNA结合蛋白（TDP-43）在患病运动神经元中从细胞核错误定位到细胞质，并与神经元内泛素化包涵体相关联。在此，我们研究了三种突变型SOD1转基因小鼠品系（G93A、G37R和G85R）中的TDP-43免疫反应性，并与一例散发性ALS病例以及两例携带SOD1、A4T和I113T突变的家族性ALS病例中的标记情况进行了比较。我们的研究结果表明，在突变型SOD1转基因小鼠的运动神经元中，TDP-43没有错误定位到细胞质，也没有与泛素化包涵体相关联。相比之下，在ALS病例中发现了TDP-43错误定位到细胞质并与泛素化包涵体相关联，包括那些携带SOD1突变的病例。有趣的是，TDP-43与泛素化透明聚集体包涵体没有关联，后者是与携带SOD1突变的ALS病例密切相关的病理学特征。我们的研究结果表明，突变型SOD1转基因小鼠中运动神经元变性的过程不太可能涉及人类疾病中描述的TDP-43异常。
