Faber Peter W, Voisine Cindy, King Daphne C, Bates Emily A, Hart Anne C
Massachusetts General Hospital Cancer Center, 149-7202 13th Street, Charlestown, MA 02129, USA.
Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):17131-6. doi: 10.1073/pnas.262544899. Epub 2002 Dec 16.
Huntington's disease is a progressive neurodegenerative disease caused by a polyglutamine (polyQ) repeat expansion in the huntingtin protein [Huntington's Disease Collaborative Research Group (1993) Cell 72, 971-983]. To understand the mechanism by which polyQ repeats cause neurodegeneration and cell death, we modeled polyQ neurotoxicity in Caenorhabditis elegans. In our model, expression of N-terminal fragments of human huntingtin causes polyQ-dependent degeneration of neurons. We conducted a genetic screen to identify proteins that protect neurons from the toxic effects of expanded polyQ tracts. Loss of polyQ enhancer-1 (pqe-1) gene function strongly and specifically exacerbates neurodegeneration and cell death, whereas overexpression of a pqe-1 cDNA protects C. elegans neurons from the toxic effects of expanded huntingtin fragments. A glutamineproline-rich domain, along with a charged domain, is critical for PQE-1 protein function. Analysis of pqe-1 suggests that proteins exist that specifically protect neurons from the toxic effects of expanded polyQ disease proteins.
亨廷顿舞蹈症是一种进行性神经退行性疾病，由亨廷顿蛋白中的多聚谷氨酰胺（polyQ）重复序列扩增引起[亨廷顿舞蹈症协作研究组（1993年），《细胞》第72卷，971 - 983页]。为了了解多聚谷氨酰胺重复序列导致神经退行性变和细胞死亡的机制，我们在秀丽隐杆线虫中建立了多聚谷氨酰胺神经毒性模型。在我们的模型中，人亨廷顿蛋白N端片段的表达导致多聚谷氨酰胺依赖的神经元变性。我们进行了一项遗传筛选，以鉴定能够保护神经元免受多聚谷氨酰胺扩展片段毒性影响的蛋白质。多聚谷氨酰胺增强子-1（pqe-1）基因功能的丧失强烈且特异性地加剧了神经退行性变和细胞死亡，而pqe-1 cDNA的过表达则保护秀丽隐杆线虫神经元免受扩展的亨廷顿片段的毒性影响。一个富含谷氨酰胺 - 脯氨酸的结构域以及一个带电荷的结构域对PQE-1蛋白的功能至关重要。对pqe-1的分析表明，存在能够特异性保护神经元免受扩展的多聚谷氨酰胺疾病蛋白毒性影响的蛋白质。
