GM1 gangliosidosis is a neurodegenerative disorder caused by mutations in the GLB1 gene, which encodes lysosomal β-galactosidase. The enzyme deficiency blocks GM1 ganglioside catabolism, leading to accumulation of GM1 ganglioside and asialo-GM1 ganglioside (GA1 glycolipid) in brain. This disease can present in varying degrees of severity, with the level of residual β-galactosidase activity primarily determining the clinical course. Glb1 null mouse models, which completely lack β-galactosidase expression, exhibit a less severe form of the disease than expected from the comparable deficiency in humans, suggesting a potential species difference in the GM1 ganglioside degradation pathway. We hypothesized this difference may involve the sialidase NEU3, which acts on GM1 ganglioside to produce GA1 glycolipid. To test this hypothesis, we generated Glb1/Neu3 double KO (DKO) mice. These mice had a significantly shorter lifespan, increased neurodegeneration, and more severe ataxia than Glb1 KO mice. Glb1/Neu3 DKO mouse brains exhibited an increased GM1 ganglioside to GA1 glycolipid ratio compared with Glb1 KO mice, indicating that NEU3 mediated GM1 ganglioside to GA1 glycolipid conversion in Glb1 KO mice. The expression of genes associated with neuroinflammation and glial responses were enhanced in Glb1/Neu3 DKO mice compared with Glb1 KO mice. Mouse NEU3 more efficiently converted GM1 ganglioside to GA1 glycolipid than human NEU3 did. Our findings highlight NEU3's role in ameliorating the consequences of Glb1 deletion in mice, provide insights into NEU3's differential effects between mice and humans in GM1 gangliosidosis, and offer a potential therapeutic approach for reducing toxic GM1 ganglioside accumulation in GM1 gangliosidosis patients.

中文翻译：

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唾液酸酶 NEU3 对 GM1 神经节苷脂的作用对 GM1 神经节苷脂沉积症具有神经保护作用。

GM1 神经节苷脂沉积症是一种由 GLB1 基因突变引起的神经退行性疾病，该基因编码溶酶体 β-半乳糖苷酶。该酶的缺乏会阻碍 GM1 神经节苷脂分解代谢，导致 GM1 神经节苷脂和去唾液酸-GM1 神经节苷脂（GA1 糖脂）在大脑中积聚。这种疾病的严重程度各不相同，残留的 β-半乳糖苷酶活性水平主要决定临床病程。Glb1缺失小鼠模型完全缺乏β-半乳糖苷酶表达，其疾病形式比人类类似缺陷所预期的疾病形式要轻，这表明GM1神经节苷脂降解途径中存在潜在的物种差异。我们假设这种差异可能涉及唾液酸酶 NEU3，它作用于 GM1 神经节苷脂以产生 GA1 糖脂。为了验证这一假设，我们生成了 Glb1/Neu3 双 KO (DKO) 小鼠。与 Glb1 KO 小鼠相比，这些小鼠的寿命显着缩短，神经变性增加，共济失调更严重。与 Glb1 KO 小鼠相比，Glb1/Neu3 DKO 小鼠大脑中 GM1 神经节苷脂与 GA1 糖脂的比例增加，表明 NEU3 介导 Glb1 KO 小鼠中 GM1 神经节苷脂向 GA1 糖脂的转化。与 Glb1 KO 小鼠相比，Glb1/Neu3 DKO 小鼠中与神经炎症和神经胶质反应相关的基因表达增强。小鼠 NEU3 比人类 NEU3 更有效地将 GM1 神经节苷脂转化为 GA1 糖脂。我们的研究结果强调了 NEU3 在改善小鼠 Glb1 缺失后果中的作用，深入了解 NEU3 在小鼠和人类之间对 GM1 神经节苷脂沉积症的不同作用，并为减少 GM1 神经节苷脂沉积症患者中有毒的 GM1 神经节苷脂积累提供潜在的治疗方法。