Santarriaga Stephanie, Petersen Amber, Ndukwe Kelechi, Brandt Anthony, Gerges Nashaat, Bruns Scaglione Jamie, Scaglione Kenneth Matthew
From the Departments of Biochemistry and the Neuroscience Research Center, The Medical College of Wisconsin, Milwaukee, Wisconsin 53226 and.
the Neuroscience Research Center, The Medical College of Wisconsin, Milwaukee, Wisconsin 53226 and Cell Biology, Neurobiology, and Anatomy and.
J Biol Chem. 2015 Oct 16;290(42):25571-8. doi: 10.1074/jbc.M115.676247. Epub 2015 Sep 1.
The expression, misfolding, and aggregation of long repetitive amino acid tracts are a major contributing factor in a number of neurodegenerative diseases, including C9ORF72 amyotrophic lateral sclerosis/frontotemporal dementia, fragile X tremor ataxia syndrome, myotonic dystrophy type 1, spinocerebellar ataxia type 8, and the nine polyglutamine diseases. Protein aggregation is a hallmark of each of these diseases. In model organisms, including yeast, worms, flies, mice, rats, and human cells, expression of proteins with the long repetitive amino acid tracts associated with these diseases recapitulates the protein aggregation that occurs in human disease. Here we show that the model organism Dictyostelium discoideum has evolved to normally encode long polyglutamine tracts and express these proteins in a soluble form. We also show that Dictyostelium has the capacity to suppress aggregation of a polyglutamine-expanded Huntingtin construct that aggregates in other model organisms tested. Together, these data identify Dictyostelium as a novel model organism with the capacity to suppress aggregation of proteins with long polyglutamine tracts.
长重复氨基酸序列的表达、错误折叠和聚集是许多神经退行性疾病的主要促成因素，包括C9ORF72型肌萎缩侧索硬化症/额颞叶痴呆、脆性X震颤共济失调综合征、1型强直性肌营养不良、8型脊髓小脑共济失调以及九种多聚谷氨酰胺疾病。蛋白质聚集是这些疾病各自的一个标志。在包括酵母、线虫、果蝇、小鼠、大鼠和人类细胞在内的模式生物中，与这些疾病相关的长重复氨基酸序列的蛋白质表达重现了人类疾病中发生的蛋白质聚集。在这里，我们表明模式生物盘基网柄菌已经进化到正常编码长多聚谷氨酰胺序列并以可溶形式表达这些蛋白质。我们还表明，盘基网柄菌有能力抑制在其他测试的模式生物中聚集的多聚谷氨酰胺扩展的亨廷顿蛋白构建体的聚集。这些数据共同确定盘基网柄菌是一种新型模式生物，具有抑制长多聚谷氨酰胺序列蛋白质聚集的能力。
