Frontotemporal dementia non-sense mutation of progranulin rescued by aminoglycosides.
Frontotemporal dementia non-sense mutation of progranulin rescued by aminoglycosides.
复制标题
氨基糖甙类药物挽救的额颞叶痴呆颗粒体蛋白前体无义突变。
DOI：
10.1093/hmg/ddz280
复制
发表时间：
2020
影响因子：
3.5
通讯作者：
Zhu,Haining
中科院分区：
文献类型：
--
作者：
Kuang,Lisha;Hashimoto,Kei;Huang,EricJ;Gentry,MatthewS;Zhu,Haining
额颞性痴呆(FTD)是一种以额叶和/或颞叶进行性萎缩为特征的早发性痴呆。FTD具有很高的遗传性，原颗粒突变占不同人群病例的5%-26%。原颗粒蛋白参与内吞、分泌和溶酶体过程，但其在生理和病理条件下的功能尚不清楚。许多引起FTD的无义原颗粒突变都含有提前终止密码子(PTC)，因此原颗粒单倍体不足被认为是一种主要的疾病机制。目前，还没有有效的治疗或治疗FTD的方法。氨基糖苷类抗生素具有一种鲜为人知的功能，可以诱导真核细胞的核糖体通读PTCs产生全长蛋白质。氨基糖苷类诱导的通读策略已被用于治疗由PTCS引起的多种人类疾病。在这项研究中，我们在细胞培养系统中测试了唯一临床批准的直读小分子PTC124和11个氨基糖苷类化合物，在四个导致FTD或相关神经退行性疾病肌萎缩侧索硬化症的PTC上进行了测试。我们发现氨基糖苷类G418和庆大霉素可以挽救原颗粒蛋白R493X突变的表达。G418的疗效优于庆大霉素(50%抢救比10%)，且呈剂量和时间依赖关系。原颗粒蛋白通读蛋白显示出与野生型原颗粒蛋白相似的亚细胞定位。这些数据提供了一个令人兴奋的概念证明，氨基糖苷类或其他促进阅读的化合物是治疗由原颗粒蛋白PTC突变引起的家族性FTD的途径。
Frontotemporal dementia (FTD) is an early onset dementia characterized by progressive atrophy of the frontal and/or temporal lobes. FTD is highly heritable with mutations inprogranulinaccounting for 5–26% of cases in different populations. Progranulin is involved in endocytosis, secretion and lysosomal processes, but its functions under physiological and pathological conditions remains to be defined. Many FTD-causing non-sense progranulin mutations contain a premature termination codon (PTC), thus progranulin haploinsufficiency has been proposed as a major disease mechanism. Currently, there is no effective FTD treatment or therapy. Aminoglycosides are a class of antibiotics that possess a less-known function to induce eukaryotic ribosomal readthrough of PTCs to produce a full-length protein. The aminoglycoside-induced readthrough strategy has been utilized to treat multiple human diseases caused by PTCs. In this study, we tested the only clinically approved readthrough small molecule PTC124 and 11 aminoglycosides in a cell culture system on four PTCs responsible for FTD or a related neurodegenerative disease amyotrophic lateral sclerosis. We found that the aminoglycosides G418 and gentamicin rescued the expression of the progranulin R493X mutation. G418 was more effective than gentamicin (~50% rescue versus <10%), and the effect was dose- and time-dependent. The progranulin readthrough protein displayed similar subcellular localization as the wild-type progranulin protein. These data provide an exciting proof-of-concept that aminoglycosides or other readthrough-promoting compounds are a therapeutic avenue for familial FTD caused by progranulin PTC mutations.