Doxycycline attenuates and delays toxicity of the oculopharyngeal muscular dystrophy mutation in transgenic mice
Doxycycline attenuates and delays toxicity of the oculopharyngeal muscular dystrophy mutation in transgenic mice
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DOI：
10.1038/nm1242
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发表时间：
2005-06-01
期刊：
影响因子：
82.9
通讯作者：
Rubinsztein, DC
中科院分区：
文献类型：
--
作者：
Davies, JE;Wang, L;Rubinsztein, DC
肌营养不良是一组不同的疾病，目前还没有治愈的方法。眼咽肌营养不良(OPMD)是一种常染色体显性遗传性晚发进展性疾病，通常在第五或六十年代出现吞咽困难、上睑下垂和近端肢体无力。OPMD是由多(A)结合蛋白核1(PABPN1)基因编码区(1)的(GCG)(N)三核苷酸重复序列异常扩张引起的。在未受影响的个体中，(GCG)(6)编码10个丙氨酸的同源多聚体中的前6个丙氨酸。在大多数OPMD患者中，这个(GCG)(6)重复序列被扩展到(GCG)(8-13)，导致突变的PABPN1中有12-17个丙氨酸。PABPN1具有扩展的聚丙氨酸束，在骨骼肌纤维的核内形成由管状细丝组成的聚集体(2-4)。我们已经建立了一种OPMD的转基因小鼠模型，表现为进行性肌肉无力，伴随着骨骼肌纤维中的核内聚集体和TUNEL染色的核。这些异常的开始和严重程度被多西环素治疗大大延迟和减轻，这可能通过减少聚集性和独特的抗细胞凋亡特性发挥其治疗效果。多西环素可能是一种安全可行的治疗方法。
The muscular dystrophies are a heterogeneous group of disorders for which there are currently no cures. Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant late-onset, progressive disease that generally presents in the fifth or sixth decade with dysphagia, ptosis and proximal limb weakness. OPMD is caused by the abnormal expansion of a (GCG)(n) trinucleotide repeat in the coding region of the poly-(A) binding protein nuclear 1 (PABPN1) gene(1). In unaffected individuals, (GCG)(6) codes for the first six alanines in a homopolymeric stretch of ten alanines. In most individuals with OPMD this (GCG)(6) repeat is expanded to (GCG)(8-13), leading to a stretch of 12 - 17 alanines in mutant PABPN1. PABPN1 with an expanded polyalanine tract forms aggregates consisting of tubular filaments within the nuclei of skeletal muscle fibers(2-4). We have developed a transgenic mouse model of OPMD that manifests progressive muscle weakness accompanied by intranuclear aggregates and TUNEL-stained nuclei in skeletal muscle fibers. The onset and severity of these abnormalities were substantially delayed and attenuated by doxycycline treatment, which may exert its therapeutic effect by reducing aggregates and by distinct antiapoptotic properties. Doxycycline may represent a safe and feasible therapeutic for this disease.