Xu TianMeng, Heon-Roberts Rachel, Moore Travis, Dubot Patricia, Pan Xuefang, Guo Tianlin, Cairo Christopher W, Holley Rebecca J, Bigger Brian, Durcan Thomas M, Levade Thierry, Ausseil Jerôme, Amilhon Bénédicte, Gorelik Alexei, Nagar Bhushan, Khan Shaukat, Tomatsu Shunji, Sturiale Luisa, Palmigiano Angelo, Röckle Iris, Thiesler Hauke, Hildebrandt Herbert, Garozzo Domenico, Pshezhetsky Alexey V
Department of Anatomy and Cell Biology, McGill University, Montreal, Canada.
Department of Paediatrics, CHU Sainte-Justine, Montreal, Canada.
J Clin Invest. 2025 Jun 17. doi: 10.1172/JCI177430.
Mucopolysaccharidoses (MPS) are lysosomal storage diseases caused by defects in catabolism of glycosaminoglycans. MPS I, II, III and VII, associated with lysosomal accumulation of heparan sulphate (HS), manifest with neurological deterioration and currently lack effective treatments. We report that neuraminidase 1 (NEU1) activity is drastically reduced in brain tissues of neurological MPS patients and mouse models but not in neurological lysosomal disorders without HS storage. Accumulated HS disrupts the lysosomal multienzyme complex of NEU1 with cathepsin A (CTSA), β-galactosidase (GLB1) and glucosamine-6-sulfate sulfatase (GALNS) leading to NEU1 deficiency and partial GLB1 and GALNS deficiencies in cortical tissues and iPSC-derived cortical neurons of neurological MPS patients. Increased sialylation of N-linked glycans in brains of MPS patients and mice implicated insufficient processing of sialylated glycans, except for polysialic acid. Correction of NEU1 activity in MPS IIIC mice by lentiviral gene transfer ameliorated previously identified hallmarks of the disease, including memory impairment, behavioural traits, and reduced levels of excitatory synapse markers VGLUT1 and PSD95. Overexpression of NEU1 also restored levels of VGLUT1/PSD95-positive puncta in cortical iPSC-derived MPS IIIA neurons. Our results demonstrate that HS-induced secondary NEU1 deficiency and aberrant sialylation of brain glycoproteins constitute what we believe to be a novel pathological pathway in neurological MPS spectrum crucially contributing to CNS pathology.
黏多糖贮积症（MPS）是由糖胺聚糖分解代谢缺陷引起的溶酶体贮积病。与硫酸乙酰肝素（HS）溶酶体积聚相关的MPS I、II、III和VII表现为神经功能恶化，目前缺乏有效治疗方法。我们报告称，神经氨酸酶1（NEU1）活性在神经型MPS患者和小鼠模型的脑组织中大幅降低，但在无HS贮积的神经型溶酶体疾病中则未降低。积累的HS破坏了NEU1与组织蛋白酶A（CTSA）、β-半乳糖苷酶（GLB1）和氨基葡萄糖-6-硫酸酯酶（GALNS）的溶酶体多酶复合物，导致神经型MPS患者的皮质组织和诱导多能干细胞衍生的皮质神经元中NEU1缺乏以及部分GLB1和GALNS缺乏。MPS患者和小鼠大脑中N-连接聚糖的唾液酸化增加，这意味着除了聚唾液酸外，唾液酸化聚糖的加工不足。通过慢病毒基因转移纠正MPS IIIC小鼠中的NEU1活性改善了先前确定的疾病特征，包括记忆障碍、行为特征以及兴奋性突触标记物VGLUT1和PSD95水平降低。NEU1的过表达还恢复了皮质诱导多能干细胞衍生的MPS IIIA神经元中VGLUT1/PSD95阳性斑点的水平。我们的结果表明，HS诱导的继发性NEU1缺乏和脑糖蛋白异常唾液酸化构成了我们认为是神经型MPS谱系中一种新的病理途径，对中枢神经系统病理至关重要。
