Interaction between alpha-COP and SMN ameliorates disease phenotype in a mouse model of spinal muscular atrophy.
Interaction between alpha-COP and SMN ameliorates disease phenotype in a mouse model of spinal muscular atrophy.
复制标题
α-COP 和 SMN 之间的相互作用可改善脊髓性肌萎缩小鼠模型的疾病表型。
DOI：
10.1016/j.bbrc.2019.04.176
复制
发表时间：
2019
影响因子：
3.1
通讯作者：
Androphy,ElliotJ
中科院分区：
文献类型：
--
作者：
Custer,SaraK;Astroski,JacobW;Li,HongXia;Androphy,ElliotJ
我们报告了α-COP蛋白的表达挽救了严重脊髓肌萎缩症小鼠的疾病表型。将表达α-COP的慢病毒颗粒直接注射到目的基因纯系小鼠的睾丸中，导致精子干细胞感染。α-COP在脑、骨骼肌和脊髓中稳定表达，不改变SMN蛋白水平。转α-COP基因的SMA小鼠的存活时间显著长于未转α-COP基因的小鼠，并且在出生后第15天显示出体重增加和正常的肌肉形态。我们以前报道过，在缺乏SMN的细胞中，需要结合SMN和SMN-COP来恢复轴突生长，我们在这里也报道了类似的发现。慢病毒介导的外显子2b双赖氨酸区突变的SMN的转基因表达不能挽救SMA的表型，尽管突变的SMN蛋白在脑、肌肉和脊髓中有较强的表达。这些结果表明，α-COP在哺乳动物和脊椎动物模型中是一种有效的SMA疾病表型修饰物，是未来SMN非依赖性治疗干预措施发展的潜在靶点。
We report that expression of the α-COP protein rescues disease phenotype in a severe mouse model of Spinal Muscular Atrophy (SMA). Lentiviral particles expressing α-COP were injected directly into the testes of genetically pure mouse strain of interest resulting in infection of the spermatagonial stem cells. α-COP was stably expressed in brain, skeletal muscle, and spinal cord without altering SMN protein levels. SMA mice transgenic for α-COP live significantly longer than their non-transgenic littermates, and showed increased body mass and normal muscle morphology at postnatal day 15. We previously reported that binding between SMN and α-COP is required for restoration of neurite outgrowth in cells lacking SMN, and we report similar finding here. Lentiviral-mediated transgenic expression of SMN where the dilysine domain in exon 2b was mutated was not able to rescue the SMA phenotype despite robust expression of the mutant SMN protein in brain, muscle and spinal cord. These results demonstrate that α-COP is a validated modifier of SMA disease phenotype in a mammalian, vertebrate model and is a potential target for development of future SMN-independent therapeutic interventions.
使用 c8-辛基柱通过离子对反相液相色谱和安培检测分析儿茶酚胺。
影响因子：
4.1
作者：
R. L. Michaud;M. Bannon;R. Roth
通讯作者：
R. Roth