Department of Biological Sciences, The George Washington University, Science and Engineering Hall 6000, 800 22nd St. N.W., Washington DC, 20052, USA; Institute for Neuroscience, The George Washington University, 636 Ross Hall, 2300 I St. N.W. Washington DC, 20052, USA.
Department of Biological Sciences, The George Washington University, Science and Engineering Hall 6000, 800 22nd St. N.W., Washington DC, 20052, USA.
Neurosci Lett. 2019 Jun 21;704:212-219. doi: 10.1016/j.neulet.2019.04.016. Epub 2019 Apr 8.
Human Islet Amyloid Polypeptide or amylin is a neuroendocrine peptide with important endocrine and paracrine functions. Excessive production and accumulation of human amylin in the pancreas can lead to its aggregation and apoptosis of islet β-cells. Amylin has been shown to function within the central nervous system to decrease food intake, and more recently, it has been revealed that amylin is directly transcribed from neurons of the central nervous system, including the hypothalamus, arcuate nucleus, medial preoptic area, and nucleus accumbens. These findings alter the current model of how amylin targets the nervous system, and as a result may lead to obesity and type II diabetes mellitus. Here we set out to use Caenorhabditis elegans as an inducible in vivo model system to study the effects of amylin overexpression in tissues that include the nervous system. We profiled the transcriptional changes in transgenic animals expressing human amylin through RNA-seq. Using this genome-wide approach our results revealed for the first time that expression of human amylin in tissues including the nervous system induce diverse physiological responses in various signaling pathways. From our characterization of transgenic C. elegans animals expressing human amylin, we also observed specific defects in neural developmental programs as well as sensory behavior. Taken together, our data demonstrate the utility of using C. elegans as a valuable in vivo model to study human amylin toxicity.
人胰岛淀粉样多肽或胰岛淀粉素有重要的内分泌和旁分泌功能的神经内分泌肽。胰岛β细胞中过量产生和积累的人胰岛淀粉样肽可导致其聚集和细胞凋亡。胰岛淀粉样肽已被证明在中枢神经系统中发挥作用，可减少食物摄入，最近还发现胰岛淀粉样肽直接由中枢神经系统的神经元转录，包括下丘脑、弓状核、视前内侧区和伏隔核。这些发现改变了胰岛淀粉样肽靶向神经系统的现行模型，可能导致肥胖和 2 型糖尿病。在这里，我们利用秀丽隐杆线虫作为可诱导的体内模型系统，研究包括神经系统在内的组织中胰岛淀粉样肽过表达的影响。我们通过 RNA-seq 对表达人胰岛淀粉样肽的转基因动物进行了转录组变化分析。通过这种全基因组方法，我们的结果首次揭示，包括神经系统在内的组织中表达人胰岛淀粉样肽可诱导各种信号通路中的不同生理反应。从我们对表达人胰岛淀粉样肽的转基因秀丽隐杆线虫动物的特征描述中，我们还观察到神经发育程序和感觉行为的特定缺陷。总之，我们的数据表明，秀丽隐杆线虫可作为研究人胰岛淀粉样肽毒性的有价值的体内模型。
