Malaspina A, Kaushik N, de Belleroche J
Department of Neuromuscular Diseases, Division of Neuroscience and Psychological Medicine, Imperial College School of Medicine, London, England.
J Neurochem. 2000 Dec;75(6):2511-20. doi: 10.1046/j.1471-4159.2000.0752511.x.
We have recently isolated a 2.2-kb cDNA clone (1C5) from a human spinal cord cDNA library with partial identity to the 14-3-3 protein mRNA encoding the theta protein (YWHAQ). 14-3-3 protein transcripts are highly expressed in large projection neurones of the hippocampus, cerebellum, and spinal cord and have been found to be significantly up-regulated in rat motor neurones following hypoglossal nerve axotomy. In this study we investigated whether the 1C5 transcript (YWHAQ) isolated from spinal cord was involved in amyotrophic lateral sclerosis (ALS). We found a significant up-regulation of 1C5 (YWHAQ) in lumbar spinal cord from patients with sporadic ALS compared with controls, with the highest levels of expression being found in individuals with predominant lower motor neurone involvement. A 6-bp tandem repeat in the 5'-untranslated region of the gene was found to be polymorphic, but no significant association with disease was found following genomic analysis of this region. The localisation of 1C5 (YWHAQ) to chromosome 2 was determined and coincides with that reported for clone HS1 (EMBL accession no. X57347). These results show the marked up-regulation of the 14-3-3 isoform (YWHAQ) in ALS spinal cord and indicate the involvement of a potential 14-3-3-mediated survival pathway in the pathogenesis of ALS.
我们最近从人脊髓cDNA文库中分离出一个2.2 kb的cDNA克隆（1C5），它与编码θ蛋白（YWHAQ）的14-3-3蛋白mRNA有部分同源性。14-3-3蛋白转录本在海马体、小脑和脊髓的大型投射神经元中高度表达，并且已发现在舌下神经切断术后大鼠运动神经元中显著上调。在本研究中，我们调查了从脊髓中分离出的1C5转录本（YWHAQ）是否参与肌萎缩侧索硬化症（ALS）。我们发现，与对照组相比，散发性ALS患者腰段脊髓中1C5（YWHAQ）显著上调，在主要累及下运动神经元的个体中表达水平最高。该基因5'-非翻译区的一个6 bp串联重复序列具有多态性，但对该区域进行基因组分析后未发现与疾病有显著关联。确定了1C5（YWHAQ）定位于2号染色体，这与报道的克隆HS1（EMBL登录号X57347）一致。这些结果表明，14-3-3异构体（YWHAQ）在ALS脊髓中显著上调，提示潜在的14-3-3介导的存活途径参与了ALS的发病机制。
