ABERRANT TRANSCRIPTS IN AGE RELATED NEURAL DISORDERS

我们和其他研究人员最近证明，转录突变可能是一个重要的因素，在病理生理学的年龄相关的神经系统疾病。 异常信使RNA数量的增加，以及随之而来的蛋白质合成改变，可导致代谢功能异常和细胞死亡。 我们最近的研究发现，在散发性肌萎缩侧索硬化症（ALS）以及阿尔茨海默病（AD）中存在多种异常谷氨酸转运蛋白EAAT 2（兴奋性氨基酸转运蛋白2）转录本，包括内含子保留和外显子跳跃，这就是很好的例子。 EAAT 2是一种星形胶质细胞谷氨酸转运蛋白，是主要的谷氨酸转运蛋白。 大约60- 70%的散发性ALS患者在运动皮层和脊髓中有30- 95%的EAAT 2蛋白丢失。 异常EAAT 2转录本在ALS患者的神经病理受累区域中高度丰富。 异常EAAT 2转录物，可能是异常剪接的结果，可导致谷氨酸转运蛋白的丢失，随后细胞外谷氨酸浓度增加和兴奋性毒性神经变性。 是否还有其他基因受到影响？ 在这项初步研究中，我们建议开发一种基于代表性差异分析（RDA）的方法来识别与年龄相关的神经系统疾病大脑中的异常转录本。

We and other investigators have recently demonstrated that transcript mutation could be an important factor in the pathophysiology of age-related neurological disorders. The increase in the number of abnormal messenger RNA, with the consequent synthesis of altered proteins, can lead to abnormal metabolic function and cell death. Our recent findings of the presence of multiple aberrant glutamate transporter EAAT2 (excitatory amino acid transporter 2) transcripts, including intron-retention and exon-skipping, in sporadic amyotrophic lateral sclerosis (ALS) as well as in Alzheimer's disease (AD) are good examples. EAAT2 is an astroglial glutamate transporter and is the predominant glutamate transporter. About 60-70 percent of sporadic ALS patients have a 30-95 percent loss of EAAT2 protein in motor cortex and spinal cord. The aberrant EAAT2 transcripts were highly abundant presented in neuropathologically affected areas of ALS patients. The aberrant EAAT2 transcripts, possibly as a consequence of abnormal splicing, can lead to loss of glutamate transporters, with subsequent increase of extracellular glutamate concentration and excitotoxic neurodegeneration. Are there other genes also affected? In this pilot study, we propose to develop a method based on the representational difference analysis (RDA) to identify aberrant transcripts in age-related neurological disorder brains.