Mucopolysaccharidoses (MPSs) are a group of inherited lysosomal storage disorders associated with the deficiency of lysosomal enzymes involved in glycosaminoglycan (GAG) degradation. The resulting cellular accumulation of GAGs is responsible for widespread tissue and organ dysfunctions. The MPS III, caused by mutations in the genes responsible for the degradation of heparan sulfate (HS), includes four subtypes (A, B, C, and D) that present significant neurological manifestations such as progressive cognitive decline and behavioral disorders. The established treatments for the MPS III do not cure the disease but only ameliorate non-neurological clinical symptoms. We previously demonstrated that the natural variant of the hepatocyte growth factor NK1 reduces the lysosomal pathology and reactivates impaired growth factor signaling in fibroblasts from MPS IIIB patients. Here, we show that the recombinant NK1 is effective in rescuing the morphological and functional dysfunctions of lysosomes in a neuronal cellular model of the MPS IIIB. More importantly, NK1 treatment is able to stimulate neuronal differentiation of neuroblastoma SK-NBE cells stable silenced for the NAGLU gene causative of the MPS IIIB. These results provide the basis for the development of a novel approach to possibly correct the neurological phenotypes of the MPS IIIB as well as of other MPSs characterized by the accumulation of HS and progressive neurodegeneration.

粘多糖贮积症 (MPS) 是一组遗传性溶酶体贮积症，与参与糖胺聚糖 (GAG) 降解的溶酶体酶缺乏相关。由此产生的 GAG 细胞积累是导致广泛的组织和器官功能障碍的原因。MPS III 是由负责硫酸乙酰肝素 (HS) 降解的基因突变引起的，包括四种亚型（A、B、C 和 D），它们表现出显着的神经系统表现，例如进行性认知衰退和行为障碍。MPS III 的既定治疗方法不能治愈该疾病，而只能改善非神经系统临床症状。我们之前已经证明，肝细胞生长因子 NK1 的天然变体减少了溶酶体病理，并重新激活了 MPS IIIB 患者成纤维细胞中受损的生长因子信号传导。在这里，我们表明重组 NK1 可有效挽救 MPS IIIB 神经元细胞模型中溶酶体的形态和功能障碍。更重要的是，NK1 治疗能够刺激神经母细胞瘤 SK-NBE 细胞的神经元分化，该细胞稳定地沉默了导致 MPS IIIB 的 NAGLU 基因。这些结果为开发可能纠正 MPS IIIB 以及以 HS 积累和进行性神经变性为特征的其他 MPS 的神经学表型的新方法提供了基础。我们表明重组 NK1 可有效挽救 MPS IIIB 神经元细胞模型中溶酶体的形态和功能障碍。更重要的是，NK1 治疗能够刺激神经母细胞瘤 SK-NBE 细胞的神经元分化，该细胞稳定地沉默了导致 MPS IIIB 的 NAGLU 基因。这些结果为开发可能纠正 MPS IIIB 以及以 HS 积累和进行性神经变性为特征的其他 MPS 的神经学表型的新方法提供了基础。我们表明重组 NK1 可有效挽救 MPS IIIB 神经元细胞模型中溶酶体的形态和功能障碍。更重要的是，NK1 治疗能够刺激神经母细胞瘤 SK-NBE 细胞的神经元分化，该细胞稳定地沉默了导致 MPS IIIB 的 NAGLU 基因。这些结果为开发可能纠正 MPS IIIB 以及以 HS 积累和进行性神经变性为特征的其他 MPS 的神经学表型的新方法提供了基础。