Berger Tamar R, Montie Heather L, Jain Pranav, Legleiter Justin, Merry Diane E
Thomas Jefferson University, Department of Biochemistry and Molecular Biology, Philadelphia, PA, USA.
Philadelphia College of Osteopathic Medicine, Department of Bio-Medical Sciences, Philadelphia, PA, USA.
Brain Res. 2015 Dec 2;1628(Pt B):254-264. doi: 10.1016/j.brainres.2015.09.033. Epub 2015 Oct 8.
Polyglutamine-repeat disorders are part of a larger family of neurodegenerative diseases characterized by protein misfolding and aggregation. In spinal and bulbar muscular atrophy (SBMA), polyglutamine expansion within the androgen receptor (AR) causes progressive debilitating muscular atrophy and lower motor neuron loss in males. Although soluble polyglutamine-expanded aggregation species are considered toxic intermediates in the aggregation process, relatively little is known about the spectrum of structures that are formed. Here we identify novel polyglutamine-expanded AR aggregates that are SDS-soluble and bind the toxicity-predicting antibody 3B5H10. Soluble, 3B5H10-reactive aggregation species exist in low-density conformations and are larger by atomic force microscopy, suggesting that they may be less compact than later-stage, insoluble aggregates. We demonstrate disease-relevance in vivo and draw correlations with toxicity in vitro. This article is part of a Special Issue entitled SI: Neuroprotection.
聚谷氨酰胺重复序列疾病是更大的神经退行性疾病家族的一部分，其特征是蛋白质错误折叠和聚集。在脊髓延髓性肌萎缩症（SBMA）中，雄激素受体（AR）内的聚谷氨酰胺扩展导致男性进行性衰弱性肌肉萎缩和下运动神经元丧失。尽管可溶性聚谷氨酰胺扩展的聚集物种被认为是聚集过程中的有毒中间体，但对于所形成的结构谱了解相对较少。在这里，我们鉴定出新型的可被十二烷基硫酸钠（SDS）溶解并结合毒性预测抗体3B5H10的聚谷氨酰胺扩展的AR聚集体。可溶性、与3B5H10反应的聚集物种以低密度构象存在，并且通过原子力显微镜观察更大，这表明它们可能比后期的不溶性聚集体更不紧密。我们在体内证明了与疾病的相关性，并在体外建立了与毒性的相关性。本文是名为“SI：神经保护”的特刊的一部分。
