Brain Transcriptome Analysis Links Deficiencies of Stress-Responsive Proteins to the Pathomechanism of Kii ALS/PDC
Brain Transcriptome Analysis Links Deficiencies of Stress-Responsive Proteins to the Pathomechanism of Kii ALS/PDC
复制标题
DOI：
10.3390/antiox9050423
复制
发表时间：
2020-05-01
期刊：
影响因子：
7
通讯作者：
Kokubo, Yasumasa
中科院分区：
文献类型：
--
作者：
Morimoto, Satoru;Ishikawa, Mitsuru;Kokubo, Yasumasa
肌萎缩侧索硬化和帕金森痴呆综合征（ALS/PDC）是日本纪伊半岛特有的地方性神经退行性疾病。为了收集对Kii ALS/PDC的病理机制的新见解，我们对患者大脑进行了转录组分析。我们从三个没有神经退行性疾病的个体、三个患有阿尔茨海默病的患者和21个患有Kii ALS/PDC的患者制备冷冻脑，然后从脑灰质和白色组织获得微阵列数据。微阵列结果显示，与热休克蛋白，DNA结合/损伤，衰老相关的基因的表达水平显着改变与ALS/PDC患者与健康人相比。ALS型脑中观察到的RNA表达模式与PDC型脑相似。此外，通路和网络分析表明，ALS/PDC的分子机制可能与线粒体，核糖体和突触囊泡周期的氧化磷酸化有关;特别是，这些机制的上游调节因子可能存在于突触和突触运输过程中。此外，ALS型和PDC型之间的表型差异进行了观察，基于HLA单倍型。总之，确定应激反应蛋白，突触功能障碍，ALS/PDC在纪伊半岛的发病机制之间的关系可能会提供这种神秘的疾病的新的理解。
Amyotrophic lateral sclerosis and Parkinsonism-dementia complex (ALS/PDC) is a unique endemic neurodegenerative disease, with high-incidence foci in Kii Peninsula, Japan. To gather new insights into the pathological mechanisms underlying Kii ALS/PDC, we performed transcriptome analyses of patient brains. We prepared frozen brains from three individuals without neurodegenerative diseases, three patients with Alzheimer's disease, and 21 patients with Kii ALS/PDC, and then acquired microarray data from cerebral gray and white matter tissues. Microarray results revealed that expression levels of genes associated with heat shock proteins, DNA binding/damage, and senescence were significantly altered in patients with ALS/PDC compared with healthy individuals. The RNA expression pattern observed for ALS-type brains was similar to that of PDC-type brains. Additionally, pathway and network analyses indicated that the molecular mechanism underlying ALS/PDC may be associated with oxidative phosphorylation of mitochondria, ribosomes, and the synaptic vesicle cycle; in particular, upstream regulators of these mechanisms may be found in synapses and during synaptic trafficking. Furthermore, phenotypic differences between ALS-type and PDC-type were observed, based on HLA haplotypes. In conclusion, determining the relationship between stress-responsive proteins, synaptic dysfunction, and the pathogenesis of ALS/PDC in the Kii peninsula may provide new understanding of this mysterious disease.