This work employs adult polyglucosan body disease (APBD) models to explore the efficacy and mechanism of action of the polyglucosan-reducing compound 144DG11. APBD is a glycogen storage disorder (GSD) caused by glycogen branching enzyme (GBE) deficiency causing accumulation of poorly branched glycogen inclusions called polyglucosans. 144DG11 improved survival and motor parameters in a GBE knockin (Gbe^ys/ys) APBD mouse model. 144DG11 reduced polyglucosan and glycogen in brain, liver, heart, and peripheral nerve. Indirect calorimetry experiments revealed that 144DG11 increases carbohydrate burn at the expense of fat burn, suggesting metabolic mobilization of pathogenic polyglucosan. At the cellular level, 144DG11 increased glycolytic, mitochondrial, and total ATP production. The molecular target of 144DG11 is the lysosomal membrane protein LAMP1, whose interaction with the compound, similar to LAMP1 knockdown, enhanced autolysosomal degradation of glycogen and lysosomal acidification. 144DG11 also enhanced mitochondrial activity and modulated lysosomal features as revealed by bioenergetic, image-based phenotyping and proteomics analyses. As an effective lysosomal targeting therapy in a GSD model, 144DG11 could be developed into a safe and efficacious glycogen and lysosomal storage disease therapy.

中文翻译：

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通过增强自噬糖原分解代谢缓解聚葡萄糖储存障碍


本工作采用成人多聚葡萄糖体疾病（APBD）模型来探索多聚葡萄糖还原化合物144DG11的功效和作用机制。 APBD 是一种糖原储存障碍 (GSD)，由糖原分支酶 (GBE) 缺乏引起，导致分支不良的糖原内含物（称为聚葡聚糖）积聚。 144DG11 改善了 GBE 敲入 (Gbe ^ys/ys ) APBD 小鼠模型的存活率和运动参数。 144DG11 减少脑、肝、心脏和周围神经中的聚葡聚糖和糖原。间接量热实验表明，144DG11 以脂肪燃烧为代价增加碳水化合物燃烧，表明致病性聚葡聚糖的代谢动员。在细胞水平上，144DG11 增加了糖酵解、线粒体和总 ATP 的产生。 144DG11的分子靶点是溶酶体膜蛋白LAMP1，其与该化合物的相互作用类似于LAMP1敲低，增强糖原的自溶酶体降解和溶酶体酸化。生物能、基于图像的表型分析和蛋白质组学分析表明，144DG11 还增强了线粒体活性并调节了溶酶体特征。作为GSD模型中有效的溶酶体靶向疗法，144DG11可以开发成安全有效的糖原和溶酶体贮积病疗法。