ABERRANT TRANSCRIPTS IN AGE RELATED NEURAL DISORDERS

年龄相关神经疾病的异常转录

• 批准号: 6224286
• 负责人: CHIEN-LIANG GLENN LIN
• 金额: $ 7.3万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6224286
• 关键词: Alzheimer's disease; RNA splicing; aging; amyotrophic lateral sclerosis; brain disorder diagnosis; brain metabolism; cell death; gene mutation; genetic transcription; glutamate transporter; human tissue; introns; method development; neural degeneration; neuropathology; postmortem; representational difference analysis

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.

我们和其他研究人员最近证明，转录本突变可能是与年龄相关的神经系统疾病病理生理学的一个重要因素。异常信使RNA数量增加，随之合成改变的蛋白质，可导致代谢功能异常和细胞死亡。我们最近发现，在散发性肌萎缩性侧索硬化症（ALS）和阿尔茨海默病（AD）中存在多种异常的谷氨酸转运蛋白EAAT2（兴奋性氨基酸转运蛋白2）转录物，包括内含子保留和外显子跳跃，就是很好的例子。EAAT2是星形胶质谷氨酸转运蛋白，是主要的谷氨酸转运蛋白。大约60- 70%的散发性肌萎缩侧索硬化症患者在运动皮层和脊髓中丢失了30- 95%的EAAT2蛋白。异常的EAAT2转录本在ALS患者的神经病理病变区域高度丰富。异常的EAAT2转录本，可能是剪接异常的结果，可导致谷氨酸转运体的丢失，随后细胞外谷氨酸浓度增加和兴奋性毒性神经变性。还有其他基因也受到影响吗？在这项初步研究中，我们提出了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。