Dystroglycanopathy, a subgroup of muscular dystrophies, is characterized by hypoglycosylation of α-dystroglycan (α-DG), which reduces its laminin-binding activity to extracellular matrix proteins, causing progressive loss of muscle integrity and function. Mutations in the fukutin-related protein (FKRP) gene are the most common causes of dystroglycanopathy. FKRP transfers ribitol-5-phosphate to the O-mannosyl glycan on α-DG from substrate cytidine diphosphate (CDP)-ribitol, which is synthesized by isoprenoid synthase domain-containing protein (ISPD). We previously reported that oral administration of ribitol restores therapeutic levels of functional glycosylation of α-DG (F-α-DG) in a FKRP mutant mouse model. Here we examine the contribution of adeno-associated virus (AAV)-mediated overexpression of ISPD to the levels of CDP-ribitol and F-α-DG with and without ribitol supplementation in the disease model. ISPD overexpression alone and in combination with ribitol improves dystrophic phenotype. Furthermore, the combined approach of ribitol and ISPD acts synergistically, increasing F-α-DG up to 40% of normal levels in cardiac muscle and more than 20% in limb and diaphragm. The results suggest that low levels of substrate limit production of CDP-ribitol, and endogenous ISPD also becomes a limiting factor in the presence of a supraphysiological concentration of ribitol. Our data support further investigation of the regulatory pathway for enhancing efficacy of ribitol supplement to FKRP-related dystroglycanopathy.

中文翻译：

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ISPD过表达增强了营养不良性FKRP突变小鼠中利比托尔诱导的α-二糖基聚糖的糖基化。

肌营养不良症是肌营养不良症的一个子组，其特征在于α-肌营养不良糖（α-DG）的糖基过低，降低了其层粘连蛋白与细胞外基质蛋白的结合活性，导致肌肉完整性和功能的逐渐丧失。福建蛋白相关蛋白（FKRP）基因的突变是营养不良性糖尿病的最常见原因。FKRP从底物胞苷二磷酸（CDP）-核糖醇将核糖基5-磷酸转移至α-DG上的O-甘露糖基聚糖，后者是由含类异戊二烯合酶结构域的蛋白质（ISPD）合成的。我们先前曾报道，在FKRP突变小鼠模型中，口服核糖醇可恢复α-DG（F-α-DG）的功能性糖基化治疗水平。在这里，我们研究了在疾病模型中添加或不添加核糖醇的情况下，腺相关病毒（AAV）介导的ISPD过表达对CDP-核糖醇和F-α-DG水平的影响。ISPD单独或与核糖醇联合过表达可改善营养不良的表型。此外，核糖醇和ISPD的组合方法具有协同作用，使F-α-DG的心肌水平增加至正常水平的40％，肢体和diaphragm肌的水平超过20％。结果表明，低水平的底物限制了CDP-核糖醇的产生，并且在存在超生理学浓度的核糖醇的情况下，内源性ISPD也成为限制因素。我们的数据支持对增强核糖醇补充剂对FKRP相关性营养失调症的功效的调节途径的进一步研究。