Cytogenetics Laboratory, Department of Zoology, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India.
Genetics. 2013 Nov;195(3):857-70. doi: 10.1534/genetics.113.155077. Epub 2013 Sep 13.
Trinucleotide CAG repeat disorders are caused by expansion of polyglutamine (polyQ) domains in certain proteins leading to fatal neurodegenerative disorders and are characterized by accumulation of inclusion bodies in the neurons. Clearance of these inclusion bodies holds the key to improve the disease phenotypes, which affects basic cellular processes such as transcription, protein degradation and cell signaling. In the present study, we show that P-glycoprotein (P-gp), originally identified as a causative agent of multidrug-resistant cancer cells, plays an important role in ameliorating the disease phenotype. Using a Drosophila transgenic strain that expresses a stretch of 127 glutamine repeats, we demonstrate that enhancing P-gp levels reduces eye degeneration caused by expression of polyQ, whereas reducing it increases the severity of the disease. Increase in polyQ inclusion bodies represses the expression of mdr genes, suggesting a functional link between P-gp and polyQ. P-gp up-regulation restores the defects in the actin organization and precise array of the neuronal connections caused by inclusion bodies. β-Catenin homolog, Armadillo, also interacts with P-gp and regulates the accumulation of inclusion bodies. These results thus show that P-gp and polyQ interact with each other, and changing P-gp levels can directly affect neurodegeneration.
三核苷酸 CAG 重复疾病是由某些蛋白质中多聚谷氨酰胺（polyQ）结构域的扩展引起的，导致致命的神经退行性疾病，其特征是神经元中包含体的积累。清除这些包含体是改善疾病表型的关键，这会影响转录、蛋白质降解和细胞信号等基本细胞过程。在本研究中，我们表明，最初被确定为多药耐药癌细胞致病因子的 P-糖蛋白（P-gp）在改善疾病表型方面发挥着重要作用。我们使用一种在果蝇中转基因表达 127 个谷氨酰胺重复序列的品系，证明增强 P-gp 水平可以减轻由 polyQ 表达引起的眼睛退化，而降低其水平会增加疾病的严重程度。polyQ 包含体的增加抑制了 mdr 基因的表达，表明 P-gp 和 polyQ 之间存在功能联系。P-gp 的上调恢复了由包含体引起的肌动蛋白组织和神经元连接的精确排列的缺陷。β-连环蛋白同源物 Armadillo 也与 P-gp 相互作用，并调节包含体的积累。因此，这些结果表明 P-gp 和 polyQ 相互作用，改变 P-gp 水平可以直接影响神经退行性变。
