Most of the patients affected by neuronopathic forms of Mucopolysaccharidosis type II (MPS II), a rare lysosomal storage disorder caused by defects in iduronate-2-sulfatase (IDS) activity, exhibit early neurological defects associated with white matter lesions and progressive behavioural abnormalities. While neuronal degeneration has been largely described in experimental models and human patients, more subtle neuronal pathogenic defects remain still underexplored. In this work, we discovered that the axon guidance receptor Deleted in Colorectal Cancer (Dcc) is significantly dysregulated in the brain of ids mutant zebrafish since embryonic stages. In addition, thanks to the establishment of neuronal-enriched primary cell cultures, we identified defective proteasomal degradation as one of the main pathways underlying Dcc upregulation in ids mutant conditions. Furthermore, ids mutant fish-derived primary neurons displayed higher levels of polyubiquitinated proteins and P62, suggesting a wider defect in protein degradation. Finally, we show that ids mutant larvae display an atypical response to anxiety-inducing stimuli, hence mimicking one of the characteristic features of MPS II patients. Our study provides an additional relevant frame to MPS II pathogenesis, supporting the concept that multiple developmental defects concur with early childhood behavioural abnormalities.

大多数患有神经病性 II 型粘多糖贮积症 (MPS II) 的患者表现出与白质病变和进行性行为异常相关的早期神经缺陷，这是一种罕见的溶酶体贮积症，由艾杜糖醛酸-2-硫酸酯酶 (IDS) 活性缺陷引起。虽然神经元变性已在实验模型和人类患者中得到广泛描述，但更微妙的神经元致病性缺陷仍未得到充分探索。在这项工作中，我们发现自胚胎期以来，ids突变斑马鱼大脑中结直肠癌删除的轴突导向受体 (Dcc) 就显着失调。此外，由于神经元富集的原代细胞培养物的建立，我们发现有缺陷的蛋白酶体降解是ids突变条件下 Dcc 上调的主要途径之一。此外，ids突变鱼源性初级神经元表现出更高水平的多泛素化蛋白和P62，表明蛋白质降解存在更广泛的缺陷。最后，我们发现ids突变幼虫对焦虑诱发的刺激表现出非典型反应，因此模仿了 MPS II 患者的特征之一。我们的研究为 MPS II 发病机制提供了一个额外的相关框架，支持多种发育缺陷与早期儿童行为异常相一致的概念。