A novel Caenorhabditis elegans allele, smn-1(cb131), mimicking a mild form of spinal muscular atrophy, provides a convenient drug screening platform highlighting new and pre-approved compounds.
A novel Caenorhabditis elegans allele, smn-1(cb131), mimicking a mild form of spinal muscular atrophy, provides a convenient drug screening platform highlighting new and pre-approved compounds.
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DOI：
10.1093/hmg/ddq459
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发表时间：
2011-01
影响因子：
3.5
通讯作者：
J. Sleigh;S. Buckingham;Behrooz Esmaeili;M. Viswanathan;E. Cuppen;B. Westlund;D. Sattelle
中科院分区：
文献类型：
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作者：
J. Sleigh;S. Buckingham;Behrooz Esmaeili;M. Viswanathan;E. Cuppen;B. Westlund;D. Sattelle
脊髓性肌萎缩症（SMA）是一种常染色体隐性遗传疾病，其特点是下部运动神经元选择性变性，导致肌肉萎缩，在最严重的情况下，导致瘫痪和死亡。缺失和点突变导致广泛表达的存活运动神经元（SMN）蛋白水平降低，这与一系列细胞过程有关。其发病机制尚不清楚，也没有有效的治疗方法。研究人员已经建立了几种动物模型来研究SMN的功能，包括秀丽隐杆线虫，其中SMN同源基因SMN -1的大量缺失导致神经肌肉功能障碍和幼虫死亡。虽然有用，这个零突变，smn-1(ok355)，不太适合药物筛选。我们报道了smn-1（cb131）的分离和表征，这是一种新的等位基因，编码高度保守的外显子2残基的替换，类似于在IIIb型SMA患者中发现的点突变。与smn-1零突变体相比，smn-1（cb131）动物表现出更轻微但相似的缺陷。使用自动表型系统，突变体比野生型动物游得慢。该表型用于筛选1040种化合物的文库，以寻找改善该缺陷的药物，突出显示6种用于后续测试。4-氨基吡啶、盐酸加博沙多和n-乙酰神经氨酸都至少在一个方面挽救了smn-1表型功能障碍。这些发现可能有助于加速SMA治疗药物的开发。
Spinal muscular atrophy (SMA), an autosomal recessive genetic disorder, is characterized by the selective degeneration of lower motor neurons, leading to muscle atrophy and, in the most severe cases, paralysis and death. Deletions and point mutations cause reduced levels of the widely expressed survival motor neuron (SMN) protein, which has been implicated in a range of cellular processes. The mechanisms underlying disease pathogenesis are unclear, and there is no effective treatment. Several animal models have been developed to study SMN function including the nematode, Caenorhabditis elegans, in which a large deletion in the gene homologous to SMN, smn-1, results in neuromuscular dysfunction and larval lethality. Although useful, this null mutant, smn-1(ok355), is not well suited to drug screening. We report the isolation and characterization of smn-1(cb131), a novel allele encoding a substitution in a highly conserved residue of exon 2, resembling a point mutation found in a patient with type IIIb SMA. The smn-1(cb131) animals display milder yet similar defects when compared with the smn-1 null mutant. Using an automated phenotyping system, mutants were shown to swim slower than wild-type animals. This phenotype was used to screen a library of 1040 chemical compounds for drugs that ameliorate the defect, highlighting six for subsequent testing. 4-aminopyridine, gaboxadol hydrochloride and N-acetylneuraminic acid all rescued at least one aspect of smn-1 phenotypic dysfunction. These findings may assist in accelerating the development of drugs for the treatment of SMA.