Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron
Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron
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DOI：
10.1073/pnas.96.1.179
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发表时间：
1999-01-05
影响因子：
11.1
通讯作者：
Hart, AC
中科院分区：
文献类型：
--
作者：
Faber, PW;Alter, JR;Hart, AC
在幼龄和老年秀丽隐杆线虫（Caenorhabditis elegans） ASH感觉神经元中表达含有不同长度的聚谷氨酰胺（polyQ）束的人类亨廷顿蛋白片段的效果进行了评估。含有150个残基的多q束（Htn-Q150）的亨廷顿蛋白片段的表达导致进行性ASH神经变性，但不引起细胞死亡。在共表达Htn-Q150和毒性OSM-10:：绿色荧光蛋白（OSM-10::GFP）融合蛋白亚阈剂量的ASH神经元中，观察到进行性细胞死亡和神经变性增强。Htn-Q150 huntingtin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神经元细胞的死亡需要ced-3 caspase的功能，这表明观察到的细胞死亡是凋亡性的。有趣的是，ced-3在htn - q150介导的神经退行性变中起关键作用，而在OSM10:: gfp介导的ASH神经退行性变中不起作用。Ced-3的功能对蛋白质聚集体的形成很重要，但不是必需的。最后，行为学分析表明，共表达Htn-Q150和OSM10::GFP的ASH神经元在检测神经变性、细胞死亡和蛋白聚集前3天功能受损。
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.