Trehalose reduces aggregate formation and delays pathology in a transgenic mouse model of oculopharyngeal muscular dystrophy
Trehalose reduces aggregate formation and delays pathology in a transgenic mouse model of oculopharyngeal muscular dystrophy
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DOI：
10.1093/hmg/ddi422
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发表时间：
2006-01-01
影响因子：
3.5
通讯作者：
Rubinsztein, DC
中科院分区：
文献类型：
--
作者：
Davies, JE;Sarkar, S;Rubinsztein, DC
眼咽型肌营养不良症是一种常染色体显性遗传疾病，在50或60岁时出现吞咽困难、上睑下垂和近端肢体无力。OPMD是由多聚（A）结合蛋白核1（PABPN1）编码区内的多聚丙氨酸段的异常扩增引起的。所得到的突变体PABPN1在骨骼肌纤维的细胞核内形成聚集体。我们先前已经描述了OPMD的转基因小鼠模型，其再现了人类疾病并发展伴随骨骼肌核中聚集体形成的进行性肌无力。化学分子伴侣海藻糖已被有效用于缓解亨廷顿氏病小鼠模型的症状，并被认为通过结合和稳定部分折叠的聚谷氨酰胺蛋白并抑制聚集体的形成而发挥作用。在这里，我们表明，海藻糖减少聚集体的形成和细胞模型中的突变PABPN1的毒性。此外，在OPMD转基因小鼠模型中，经口给予海藻糖可减轻肌无力，减少聚集体形成，并减少骨骼肌中TUNEL标记的细胞核数量。因此，抗聚集疗法可证明在治疗人OPMD中有效。
Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant disease that presents in the fifth or sixth decade with dysphagia, ptosis and proximal limb weakness. OPMD is caused by the abnormal expansion of a polyalanine tract within the coding region of poly(A) binding protein nuclear 1 (PABPN1). The resultant mutant PABPN1 forms aggregates within the nuclei of skeletal muscle fibres. We have previously described a transgenic mouse model of OPMD that recapitulates the human disease and develops progressive muscle weakness accompanied by the formation of aggregates in skeletal muscle nuclei. The chemical chaperone trehalose has been used effectively to alleviate symptoms in a mouse model of Huntington's disease and is thought to elicit its effect by binding and stabilizing partially folded polyglutamine proteins and inhibiting the formation of aggregates. Here, we show that trehalose reduces aggregate formation and toxicity of mutant PABPN1 in cell models. Furthermore, oral administration of trehalose attenuated muscle weakness, reduced aggregate formation and decreased the number of TUNEL-labelled nuclei in skeletal muscle in an OPMD transgenic mouse model. Thus, anti-aggregation therapy may prove effective in the treatment of human OPMD.