Wang Jiou, Xu Guilian, Li Hong, Gonzales Victoria, Fromholt David, Karch Celeste, Copeland Neal G, Jenkins Nancy A, Borchelt David R
Departement of Pathology, The John's Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Hum Mol Genet. 2005 Aug 15;14(16):2335-47. doi: 10.1093/hmg/ddi236. Epub 2005 Jul 6.
Mice expressing variants of superoxide dismutase-1 (SOD1) encoding C-terminal truncation mutations linked to familial amyotrophic lateral sclerosis (FALS) have begun to define the role of misfolding and aggregation in the pathogenesis of disease. Here, we examine transgenic mice expressing SOD1-L126Z (Z = stop-truncation of last 28 amino acids), finding that detergent-insoluble mutant protein specifically accumulates in somatodendritic compartments. Soluble forms of the SOD1-L126Z were virtually undetectable in spinal cord at any age and the levels of accumulated protein directly correlated with disease symptoms. Neither soluble nor insoluble forms of SOD1-L126Z were transported to distal axons. In vitro, small heat shock protein (Hsp) alphaB-crystallin suppressed the in vitro aggregation of SOD1-L126Z. In vivo, alphaB-crystallin immunoreactivity was most abundant in oligodendrocytes and up-regulated in astrocytes of symptomatic mice; neither of these cell-types accumulated mutant SOD1 immunoreactivity. These results suggest that damage to motor neuron cell bodies and dendrites within the spinal cord can be sufficient to induce motor neuron disease and that the activities of chaperones may modulate the cellular specificity of mutant SOD1 accumulation.
表达与家族性肌萎缩侧索硬化症（FALS）相关的编码C末端截短突变的超氧化物歧化酶-1（SOD1）变体的小鼠，已开始明确错误折叠和聚集在疾病发病机制中的作用。在此，我们研究了表达SOD1-L126Z（Z = 最后28个氨基酸的截短突变）的转基因小鼠，发现去污剂不溶性突变蛋白特异性地积聚在树突状细胞区室中。在任何年龄的脊髓中，几乎都检测不到SOD1-L126Z的可溶性形式，并且积聚蛋白的水平与疾病症状直接相关。SOD1-L126Z的可溶性和不溶性形式均未转运至远端轴突。在体外，小分子热休克蛋白（Hsp）αB-晶状体蛋白抑制了SOD1-L126Z的体外聚集。在体内，αB-晶状体蛋白免疫反应性在少突胶质细胞中最为丰富，并且在有症状小鼠的星形胶质细胞中上调；这两种细胞类型均未积累突变型SOD1免疫反应性。这些结果表明，脊髓内运动神经元细胞体和树突的损伤足以诱发运动神经元疾病，并且伴侣蛋白的活性可能调节突变型SOD1积累的细胞特异性。
