Laboratory of Diagnosis and Therapy of Lysosomal Disorders, Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128 Padova, Italy.
Fondazione Istituto di Ricerca Pediatrica "Città della Speranza", Corso Stati Uniti 4, 35127 Padova, Italy.
Cells. 2021 Dec 31;11(1):129. doi: 10.3390/cells11010129.
Deficit of the IDUA (α-L-iduronidase) enzyme causes the lysosomal storage disorder mucopolysaccharidosis type I (MPS I), a rare pediatric neurometabolic disease, due to pathological variants in the gene and is characterized by the accumulation of the undegraded mucopolysaccharides heparan sulfate and dermatan sulfate into lysosomes, with secondary cellular consequences that are still mostly unclarified. Here, we report a new fruit fly RNAi-mediated knockdown model of a homolog () displaying a phenotype mimicking some typical molecular features of Lysosomal Storage Disorders (LSD). In this study, we showed that is a vital gene in and that ubiquitous reduction of its expression leads to lethality during the pupal stage, when the precise degradation/synthesis of macromolecules, together with a functional autophagic pathway, are indispensable for the correct development to the adult stage. Tissue-specific analysis of the model showed an increase in the number and size of lysosomes in the brain and muscle. Moreover, the incorrect acidification of lysosomes led to dysfunctional lysosome-autophagosome fusion and the consequent block of autophagy flux. A concomitant metabolic drift of glycolysis and lipogenesis pathways was observed. After starvation, larvae showed a quite complete rescue of both autophagy/lysosome phenotypes and metabolic alterations. Metabolism and autophagy are strictly interconnected vital processes that contribute to maintain homeostatic control of energy balance, and little is known about this regulation in LSDs. Our results provide new starting points for future investigations on the disease's pathogenic mechanisms and possible pharmacological manipulations.
IDUA（α-L-艾杜糖苷酸酶）酶的缺乏导致溶酶体贮积症 I 型（MPS I），这是一种罕见的儿科神经代谢疾病，由于基因中的病理性变异，并以未降解的粘多糖硫酸乙酰肝素和硫酸皮肤素在溶酶体中的积累为特征，其继发的细胞后果仍大多不清楚。在这里，我们报告了一种新的果蝇 RNAi 介导的敲低模型（），其表现出类似于溶酶体贮积症（LSD）的一些典型分子特征的表型。在这项研究中，我们表明是必需基因，其表达的普遍减少导致蛹期的致死性，此时大分子的精确降解/合成以及功能自噬途径对于正确发育到成虫阶段是必不可少的。对模型的组织特异性分析显示，大脑和肌肉中的溶酶体数量和大小增加。此外，溶酶体的错误酸化导致溶酶体-自噬体融合功能障碍和自噬流的阻断。同时观察到糖酵解和脂生成途径的代谢漂移。饥饿后，幼虫的自噬/溶酶体表型和代谢改变得到了相当完全的恢复。代谢和自噬是严格相互关联的重要过程，有助于维持能量平衡的体内平衡控制，而 LSD 中对此调节知之甚少。我们的结果为未来对疾病发病机制和可能的药物干预的研究提供了新的起点。
