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首页> 美国卫生研究院文献>Nucleus >Reversal of age-dependent nuclear morphology by inhibition of prenylation does not affect lifespan in Caenorhabditis elegans
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Reversal of age-dependent nuclear morphology by inhibition of prenylation does not affect lifespan in Caenorhabditis elegans

机译：通过抑制异戊烯化作用逆转年龄相关的核形态不会影响秀丽隐杆线虫的寿命

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摘要

Fibroblasts derived from Hutchinson-Gilford progeria syndrome (HGPS) patients and dermal cells derived from healthy old humans in culture display age-dependent progressive changes in nuclear architecture due to accumulation of farnesylated lamin A. Treating human HGPS cells or mice expressing farnesylated lamin A with farnesyl transferase inhibitors (FTIs) reverses nuclear phenotypes and extends lifespan. Aging adult Caenorhabditis elegans show changes in nuclear architecture resembling those seen in HGPS fibroblasts, as well as a decline in motility, phenotypes which are also inhibited by the FTI gliotoxin. However, it was not clear whether these effects were due to loss of farnesylation or to side effects of this drug. Here, we used a different FTI, manumycin or downregulated polyprenyl synthetase with RNAi to test the roles of farnesylation in C. elegans aging. Our results show that the age-dependent changes in nuclear morphology depend on farnesylation. We also demonstrate that inhibition of farnesylation does not affect motility or lifespan, suggesting that the effects of blocking protein prenylation on nuclear morphology could be separated from their effects on motility and lifespan. These results provide further understanding of the role of lamin and farnesylation in the normal aging process and in HGPS.
机译：Hutchinson-Gilford早衰综合征（HGPS）患者的成纤维细胞和健康老年人的真皮细胞在培养中由于法尼基化层粘连蛋白A的积累而显示出年龄依赖性的核结构渐进性变化。法呢基转移酶抑制剂（FTI）可逆转核表型并延长寿命。成年的秀丽隐杆线虫显示出类似于HGPS成纤维细胞的核结构变化，以及运动性下降，其表型也受到FTI gliotoxin的抑制。但是，尚不清楚这些作用是由于法呢基化作用的丧失还是该药的副作用所致。在这里，我们使用了不同的FTI，manumycin或带有RNAi的下调聚异戊二烯基合成酶来测试法尼基化在秀丽隐杆线虫衰老中的作用。我们的结果表明，核形态的年龄依赖性变化取决于法呢基化。我们还证明，法尼基化的抑制作用不会影响运动性或寿命，这表明阻断蛋白异戊二烯化对核形态的影响可以与它们对运动性和寿命的影响分开。这些结果提供了进一步的了解，在正常的衰老过程中和HGPS中的lamin和法尼基化的作用。

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