Faber P W, Alter J R, MacDonald M E, Hart A C
Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
Proc Natl Acad Sci U S A. 1999 Jan 5;96(1):179-84. doi: 10.1073/pnas.96.1.179.
The effect of expressing human huntingtin fragments containing polyglutamine (polyQ) tracts of varying lengths was assessed in Caenorhabditis elegans ASH sensory neurons in young and old animals. Expression of a huntingtin fragment containing a polyQ tract of 150 residues (Htn-Q150) led to progressive ASH neurodegeneration but did not cause cell death. Progressive cell death and enhanced neurodegeneration were observed in ASH neurons that coexpressed Htn-Q150 and a subthreshold dose of a toxic OSM-10::green fluorescent protein (OSM-10::GFP) fusion protein. Htn-Q150 huntingtin protein fragments formed protein aggregates in ASH neurons, and the number of ASH neurons containing aggregates increased as animals aged. ASH neuronal cell death required ced-3 caspase function, indicating that the observed cell death is apoptotic. Of interest, ced-3 played a critical role in Htn-Q150-mediated neurodegeneration but not in OSM10::GFP-mediated ASH neurodegeneration. ced-3 function was important but not essential for the formation of protein aggregates. Finally, behavioral assays indicated that ASH neurons, coexpressing Htn-Q150 and OSM10::GFP, were functionally impaired at 3 days before the detection of neurodegeneration, cell death, and protein aggregates.
在年轻和年老的秀丽隐杆线虫ASH感觉神经元中评估了表达含有不同长度聚谷氨酰胺（polyQ）序列的人类亨廷顿蛋白片段的影响。表达含有150个残基的polyQ序列的亨廷顿蛋白片段（Htn-Q150）导致ASH神经元进行性神经变性，但未导致细胞死亡。在共表达Htn-Q150和亚阈值剂量的有毒OSM-10::绿色荧光蛋白（OSM-10::GFP）融合蛋白的ASH神经元中观察到进行性细胞死亡和增强的神经变性。Htn-Q150亨廷顿蛋白片段在ASH神经元中形成蛋白聚集体，并且随着动物年龄的增长，含有聚集体的ASH神经元数量增加。ASH神经元细胞死亡需要ced-3半胱天冬酶功能，表明观察到的细胞死亡是凋亡性的。有趣的是，ced-3在Htn-Q150介导的神经变性中起关键作用，但在OSM10::GFP介导的ASH神经变性中不起作用。ced-3功能对于蛋白聚集体的形成很重要但不是必需的。最后，行为分析表明，共表达Htn-Q150和OSM10::GFP的ASH神经元在检测到神经变性、细胞死亡和蛋白聚集体前3天功能受损。
