Pathological impact of SMN2 mis-splicing in adult SMA mice.
Pathological impact of SMN2 mis-splicing in adult SMA mice.
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DOI：
10.1002/emmm.201302567
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发表时间：
2013-10
影响因子：
11.1
通讯作者：
Krainer, Adrian R.
中科院分区：
文献类型：
--
作者：
Sahashi, Kentaro;Ling, Karen K. Y.;Hua, Yimin;Wilkinson, John Erby;Nomakuchi, Tomoki;Rigo, Frank;Hung, Gene;Xu, David;Jiang, Ya-Ping;Lin, Richard Z.;Ko, Chien-Ping;Bennett, C. Frank;Krainer, Adrian R.
SMN1的功能丧失突变导致脊髓性肌萎缩症（SMA），这是婴儿死亡的主要遗传原因。由于剪接缺陷，相关的SMN2基因表达功能SMN蛋白的次优水平。许多SMA患者达到成年期，也有成人发病（IV型）SMA。目前还没有成人发病SMA的动物模型，发育后SMN缺乏的组织特异性发病机制仍然难以捉摸。在这里，我们使用反义寡核苷酸（ASO）来加剧SMN2错误剪接。在成年smn2转基因小鼠脑室内注射ASO可显示成年SMA的关键方面，包括迟发性运动功能障碍和相关的组织病理学特征。SMN2错误剪接在疾病晚期增加，可能加速疾病进展。成年小鼠全身注射ASO可引起外周SMN2错误剪接并影响预后，引起肝脏和心脏明显病变，IGF1水平降低。ASO剂量反应和时间过程研究表明，成人中枢神经系统只需要中等水平的SMN，使用剪接校正ASO治疗显示出广泛的治疗时间窗口。我们描述了成人发病和早发性SMA的独特病理特征。
Loss-of-function mutations in SMN1 cause spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. The related SMN2 gene expresses suboptimal levels of functional SMN protein, due to a splicing defect. Many SMA patients reach adulthood, and there is also adult-onset (type IV) SMA. There is currently no animal model for adult-onset SMA, and the tissue-specific pathogenesis of post-developmental SMN deficiency remains elusive. Here, we use an antisense oligonucleotide (ASO) to exacerbate SMN2 mis-splicing. Intracerebroventricular ASO injection in adult SMN2-transgenic mice phenocopies key aspects of adult-onset SMA, including delayed-onset motor dysfunction and relevant histopathological features. SMN2 mis-splicing increases during late-stage disease, likely accelerating disease progression. Systemic ASO injection in adult mice causes peripheral SMN2 mis-splicing and affects prognosis, eliciting marked liver and heart pathologies, with decreased IGF1 levels. ASO dose–response and time-course studies suggest that only moderate SMN levels are required in the adult central nervous system, and treatment with a splicing-correcting ASO shows a broad therapeutic time window. We describe distinctive pathological features of adult-onset and early-onset SMA.
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影响因子：
46.9
作者：
通讯作者：
--
影响因子：
4.8
作者：
DAI, J;BAXTER, RC
通讯作者：
BAXTER, RC
DOI：
10.1523/jneurosci.5775-11.2012
发表时间：
2012-03-14
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Gogliotti RG;Quinlan KA;Barlow CB;Heier CR;Heckman CJ;Didonato CJ
通讯作者：
Didonato CJ
影响因子：
9.8
作者：
Hua, Yimin;Vickers, Timothy A;Baker, Brenda F;Bennett, C Frank;Krainer, Adrian R
通讯作者：
Krainer, Adrian R
影响因子：
3.5
作者：
Coovert, DD;Le, TT;Burghes, AHM
通讯作者：
Burghes, AHM