Attenuation of nonsense-mediated mRNA decay enhances in vivo nonsense suppression.
Attenuation of nonsense-mediated mRNA decay enhances in vivo nonsense suppression.
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DOI：
10.1371/journal.pone.0060478
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Bedwell DM
中科院分区：
文献类型：
--
作者：
Keeling KM;Wang D;Dai Y;Murugesan S;Chenna B;Clark J;Belakhov V;Kandasamy J;Velu SE;Baasov T;Bedwell DM
无义抑制疗法是治疗无义突变引起的遗传疾病的一种方法。这种治疗策略抑制在过早终止密码子（PTC）处的翻译终止，以恢复功能蛋白的表达。然而，无义介导的mRNA衰变（NMD）过程减少了含有PTC的mRNA的丰度，经常限制这种方法。在这里，我们使用了一个小鼠模型的溶酶体贮积病粘多糖样变性I-Hurler（MPS I-H），携带PTC的Idua基因座，以测试是否NMD衰减可以增强PTC抑制体内。Idua编码α-L-艾杜糖醛酸酶，一种降解糖胺聚糖（GAG）硫酸乙酰肝素和硫酸皮肤素所需的酶。我们发现NMD衰减剂NMDI-1增加了含PTC的Idua转录物的丰度。此外，与庆大霉素单独给药相比，NMDI-1与PTC抑制药物庆大霉素联合给药增强了α-L-艾杜糖醛酸酶活性，导致小鼠组织（包括大脑）中GAG蓄积的更大减少。这些结果表明，NMD衰减显著增强体内抑制治疗。
Nonsense suppression therapy is an approach to treat genetic diseases caused by nonsense mutations. This therapeutic strategy pharmacologically suppresses translation termination at Premature Termination Codons (PTCs) in order to restore expression of functional protein. However, the process of Nonsense-Mediated mRNA Decay (NMD), which reduces the abundance of mRNAs containing PTCs, frequently limits this approach. Here, we used a mouse model of the lysosomal storage disease mucopolysaccharidosis I-Hurler (MPS I-H) that carries a PTC in the Idua locus to test whether NMD attenuation can enhance PTC suppression in vivo. Idua encodes alpha-L-iduronidase, an enzyme required for degradation of the glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate. We found that the NMD attenuator NMDI-1 increased the abundance of the PTC-containing Idua transcript. Furthermore, co-administration of NMDI-1 with the PTC suppression drug gentamicin enhanced alpha-L-iduronidase activity compared to gentamicin alone, leading to a greater reduction of GAG storage in mouse tissues, including the brain. These results demonstrate that NMD attenuation significantly enhances suppression therapy in vivo.
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DOI：
10.1083/jcb.200611086
发表时间：
2007-09-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Durand S;Cougot N;Mahuteau-Betzer F;Nguyen CH;Grierson DS;Bertrand E;Tazi J;Lejeune F
通讯作者：
Lejeune F
影响因子：
16
作者：
Huang L;Lou CH;Chan W;Shum EY;Shao A;Stone E;Karam R;Song HW;Wilkinson MF
通讯作者：
Wilkinson MF
影响因子：
11.4
作者：
Linde, Liat;Kerem, Batsheva
通讯作者：
Kerem, Batsheva
影响因子：
11.2
作者：
Malik, Vinod;Rodino-Klapac, Louise R.;Mendell, Jerry R.
通讯作者：
Mendell, Jerry R.
影响因子：
30.8
作者：
Mendell, JT;Sharifi, NA;Dietz, HC
通讯作者：
Dietz, HC