Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila
Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila
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DOI：
10.1093/hmg/11.23.2895
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发表时间：
2002-11-01
影响因子：
3.5
通讯作者：
Bonini, NM
中科院分区：
文献类型：
--
作者：
Chan, HYE;Warrick, JM;Bonini, NM
脊髓延髓肌萎缩症（SBMA）是一种遗传性神经退行性疾病，由雄激素受体（AR）蛋白内的多聚谷氨酰胺[poly（Q）]重复扩增引起。我们研究了SBMA在果蝇中使用的N-末端片段的人AR蛋白。在果蝇中具有扩展的poly（Q）重复序列的致病性AR蛋白的表达导致细胞核和细胞质内含物的形成以及细胞变性，特别是在神经元组织中。我们研究了泛素依赖性修饰和蛋白酶体途径对神经变性和AR蛋白片段溶解性的影响。损害泛素/蛋白酶体途径会增强变性并降低聚（Q）蛋白的溶解度。我们的数据进一步表明，热休克蛋白70和蛋白酶体的行为在一个加性的方式来调节神经退行性变。通过SUMO-1激活酶Uba 2的突变体的过表达，我们进一步表明，当细胞SUMO-1蛋白缀合途径改变时，poly（Q）诱导的变性会加剧。这些数据表明，翻译后蛋白质修饰，包括泛素/蛋白酶体和SUMO-1途径，调节聚（Q）的发病机制。
Spinal and bulbar muscular atrophy (SBMA) is a heritable neurodegenerative disease caused by the expansion of a polyglutamine, [poly(Q)] repeat within the androgen receptor (AR) protein. We studied SBMA in Drosophila using an N-terminal fragment of the human AR protein. Expression of a pathogenic AR protein with an expanded poly(Q) repeat in Drosophila results in nuclear and cytoplasmic inclusion formation, and cellular degeneration, preferentially in neuronal tissues. We have studied the influence of ubiquitin-dependent modification and the proteasome pathway on neural degeneration and AR protein fragment solubility. Compromising the ubiquitin/proteasome pathway enhances degeneration and decreases poly(Q) protein solubility. Our data further suggest that Hsp70 and the proteasome act in an additive manner to modulate neurodegeneration. Through the over-expression of a mutant of the SUMO-1 activating enzyme Uba2, we further show that poly(Q)-induced degeneration is intensified when the cellular SUMO-1 protein conjugation pathway is altered. These data suggest that post-translational protein modification, including the ubiquitin/proteasome and the SUMO-1 pathways, modulate poly(Q) pathogenesis.