Temsirolimus Partially Rescues the Hutchinson-Gilford Progeria Cellular Phenotype
Temsirolimus Partially Rescues the Hutchinson-Gilford Progeria Cellular Phenotype
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DOI：
10.1371/journal.pone.0168988
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发表时间：
2016-12-29
期刊：
影响因子：
3.7
通讯作者：
Djabali, Karima
中科院分区：
文献类型：
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作者：
Gabriel, Diana;Gordon, Leslie B.;Djabali, Karima
Hutchinson-Gilford 综合征（HGPS，OMIM 176670）是一种罕见的过早衰老疾病，因心肌梗塞或中风导致平均年龄 14.7 岁死亡，由 LMNA 基因突变引起。核纤层蛋白除了调节 DNA 复制、DNA 转录、增殖和分化外，还有助于维持核膜的形状和稳定性。LMNA 突变导致核膜羧基末端区域缺失 50 个氨基酸。 prelamin A，产生截短的法尼基化蛋白质早老素。早老素在 HGPS 核中的积累会导致许多形态和功能变化，从而导致细胞过早衰老。逆转这种 HGPS 表型的尝试已确定雷帕霉素（一种哺乳动物雷帕霉素靶点 (mTOR) 抑制剂）是一种能够通过促进自噬和减少早老素积累来拯救 HGPS 细胞表型的药物。雷帕霉素是治疗 HGPS 疾病的明显候选药物，但很难在临床上使用。为了进一步评估雷帕霉素在蛋白质稳态、线粒体功能和 DNA 损伤程度方面的功效，我们测试了替西罗莫司，这是一种比雷帕霉素具有更有利的药代动力学特征的雷帕霉素类似物，我们报告说，替西罗莫司可降低早老素水平，增加增殖，减少畸形细胞核，并部分改善 DNA。我们的研究结果表明，未来的治疗策略应该针对 HGPS 细胞的所有功能障碍特征确定新的药物组合和治疗方案。
Hutchinson-Gilford syndrome (HGPS, OMIM 176670, a rare premature aging disorder that leads to death at an average age of 14.7 years due to myocardial infarction or stroke, is caused by mutations in the LMNA gene. Lamins help maintain the shape and stability of the nuclear envelope in addition to regulating DNA replication, DNA transcription, proliferation and differentiation. The LMNA mutation results in the deletion of 50 amino acids from the carboxy-terminal region of prelamin A, producing the truncated, farnesylated protein progerin. The accumulation of progerin in HGPS nuclei causes numerous morphological and functional changes that lead to premature cellular senescence. Attempts to reverse this HGPS phenotype have identified rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), as a drug that is able to rescue the HGPS cellular phenotype by promoting autophagy and reducing progerin accumulation. Rapamycin is an obvious candidate for the treatment of HGPS disease but is difficult to utilize clinically. To further assess rapamycin's efficacy with regard to proteostasis, mitochondrial function and the degree of DNA damage, we tested temsirolimus, a rapamycin analog with a more favorable pharmacokinetic profile than rapamycin. We report that temsirolimus decreases progerin levels, increases proliferation, reduces misshapen nuclei, and partially ameliorates DNA damage, but does not improve proteasome activity or mitochondrial dysfunction. Our findings suggest that future therapeutic strategies should identify new drug combinations and treatment regimens that target all the dysfunctional hallmarks that characterize HGPS cells.