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首页> 美国卫生研究院文献>The Journal of Neuroscience >Generation of Neuronal Intranuclear Inclusions by Polyglutamine-GFP: Analysis of Inclusion Clearance and Toxicity as a Function of Polyglutamine Length
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Generation of Neuronal Intranuclear Inclusions by Polyglutamine-GFP: Analysis of Inclusion Clearance and Toxicity as a Function of Polyglutamine Length

机译：通过聚谷氨酰胺-GFP的神经元核内包裹体的生成：包裹体清除率和毒性作为聚谷氨酰胺长度的函数分析

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Recent evidence suggests that, in huntingtin and many other proteins, polyglutamine repeats are a toxic stimulus in neurodegenerative diseases. To investigate the mechanism by which these repeats may be toxic, we transfected primary rat cerebellar granule neurons with polyglutamine-green fluorescent protein (GFP) fusion constructs containing 19 (Q19-GFP), 35 (Q35-GFP), 56 (Q56-GFP), or 80 (Q80-GFP) glutamine residues. All constructs, except Q19-GFP, aggregated within the nuclei of transfected cells in a length- and time-dependent manner. Although Q35-GFP expression led to the development of several small aggregates per cell, these aggregates were cleared or degraded, and the cells remained viable. In contrast, Q80-GFP expression resulted in one or two large aggregates and induced cell death. Caspase activation was observed after Q80-GFP aggregation, but inhibition of caspases with Boc-aspartyl(OMe)-fluoromethylketone (BAF) only served to delay, not prevent, toxicity. In addition, aggregation and toxicity were not affected by other modulators of neuronal cell death such as genetic deletion of the proapoptotic bcl-2 family memberbax or addition of the protein synthesis inhibitor cycloheximide. Lastly, nuclear condensation did not occur as part of the toxicity. These data suggest that polyglutamine-GFP expression is toxic to primary neurons but that the death is distinct from classical apoptosis.
机译：最近的证据表明，在亨廷顿蛋白和许多其他蛋白质中，聚谷氨酰胺重复序列是神经退行性疾病的一种毒性刺激。为了研究这些重复序列可能具有毒性的机制，我们用含有19（Q19-GFP），35（Q35-GFP），56（Q56-GFP）的聚谷氨酰胺-绿色荧光蛋白（GFP）融合构建体转染了原代大鼠小脑颗粒神经元。 ）或80个（Q80-GFP）谷氨酰胺残基。除Q19-GFP外，所有构建体均以长度和时间依赖性方式聚集在转染细胞的细胞核内。尽管Q35-GFP表达导致每个细胞形成几个小的聚集体，但这些聚集体被清除或降解，并且细胞保持活力。相反，Q80-GFP表达导致一个或两个大的聚集体并诱导细胞死亡。 Q80-GFP聚集后观察到胱天蛋白酶激活，但用Boc-天冬氨酰（OMe）-氟甲基酮（BAF）抑制胱天蛋白酶仅起到延缓而非预防毒性的作用。另外，聚集和毒性不受神经元细胞死亡的其他调节剂的影响，例如促凋亡的bcl-2家族成员的基因缺失或添加蛋白质合成抑制剂环己酰亚胺。最后，没有发生核凝聚作为毒性的一部分。这些数据表明，聚谷氨酰胺-GFP表达对原代神经元有毒性，但死亡与经典凋亡不同。

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