Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Dis Model Mech. 2020 Aug 27;13(8):dmm044891. doi: 10.1242/dmm.044891.
Nonsense-mediated mRNA decay (NMD) targets mRNAs that contain a premature termination codon (PTC) for degradation, preventing their translation. By altering the expression of PTC-containing mRNAs, NMD modulates the inheritance pattern and severity of genetic diseases. NMD also limits the efficiency of suppressing translation termination at PTCs, an emerging therapeutic approach to treat genetic diseases caused by in-frame PTCs (nonsense mutations). Inhibiting NMD may help rescue partial levels of protein expression. However, it is unclear whether long-term, global NMD attenuation is safe. We hypothesize that a degree of NMD inhibition can be safely tolerated after completion of prenatal development. To test this hypothesis, we generated a novel transgenic mouse that expresses an inducible, dominant-negative form of human () to inhibit NMD in mouse tissues by different degrees, allowing us to examine the effects of global NMD inhibition A thorough characterization of these mice indicated that expressing at levels that promote relatively moderate to strong NMD inhibition in most tissues for a 1-month period produced modest immunological and bone alterations. In contrast, 1 month of expression to promote more modest NMD inhibition in most tissues did not produce any discernable defects, indicating that moderate global NMD attenuation is generally well tolerated in non-neurological somatic tissues. Importantly, a modest level of NMD inhibition that produced no overt abnormalities was able to significantly enhance PTC suppression. These results suggest that safe levels of NMD attenuation are likely achievable, and this can help rescue protein deficiencies resulting from PTCs.
无义介导的 mRNA 降解（NMD）靶向含有过早终止密码子（PTC）的 mRNA 进行降解，从而阻止其翻译。通过改变含有 PTC 的 mRNA 的表达，NMD 调节遗传疾病的遗传模式和严重程度。NMD 还限制了在 PTC 处抑制翻译终止的效率，这是一种新兴的治疗方法，用于治疗由框内 PTC（无义突变）引起的遗传疾病。抑制 NMD 可能有助于挽救部分蛋白质表达水平。然而，尚不清楚长期、全面的 NMD 衰减是否安全。我们假设，在产前发育完成后，可以安全地耐受一定程度的 NMD 抑制。为了验证这一假设，我们生成了一种新型转基因小鼠，该小鼠表达一种可诱导的、显性负形式的人类 （），通过不同程度抑制小鼠组织中的 NMD，使我们能够检查全面抑制 NMD 的影响。对这些小鼠进行的全面表征表明，在大多数组织中表达 ，以促进相对中度至强烈的 NMD 抑制水平 1 个月，会导致适度的免疫和骨骼改变。相比之下，在大多数组织中表达 1 个月以促进更适度的 NMD 抑制不会产生任何明显的缺陷，表明在非神经体细胞组织中，适度的全球 NMD 衰减通常是可以耐受的。重要的是，产生无明显异常的适度 NMD 抑制水平能够显著增强 PTC 抑制。这些结果表明，安全的 NMD 衰减水平可能是可以实现的，这可以帮助挽救由 PTC 引起的蛋白质缺乏。
