Research, BioMarin Pharmaceutical Inc., Novato, CA, United States of America.
University of Massachusetts Medical School, Worcester, MA, United States of America.
PLoS One. 2020 Dec 1;15(12):e0243006. doi: 10.1371/journal.pone.0243006. eCollection 2020.
β-hexosaminidase is an enzyme responsible for the degradation of gangliosides, glycans, and other glycoconjugates containing β-linked hexosamines that enter the lysosome. GM2 gangliosidoses, such as Tay-Sachs and Sandhoff, are lysosomal storage disorders characterized by β-hexosaminidase deficiency and subsequent lysosomal accumulation of its substrate metabolites. These two diseases result in neurodegeneration and early mortality in children. A significant difference between these two disorders is the accumulation in Sandhoff disease of soluble oligosaccharide metabolites that derive from N- and O-linked glycans. In this paper we describe our results from a longitudinal biochemical study of a feline model of Sandhoff disease and an ovine model of Tay-Sachs disease to investigate the accumulation of GM2/GA2 gangliosides, a secondary biomarker for phospholipidosis, bis-(monoacylglycero)-phosphate, and soluble glycan metabolites in both tissue and fluid samples from both animal models. While both Sandhoff cats and Tay-Sachs sheep accumulated significant amounts of GM2 and GA2 gangliosides compared to age-matched unaffected controls, the Sandhoff cats having the more severe disease, accumulated larger amounts of gangliosides compared to Tay-Sachs sheep in their occipital lobes. For monitoring glycan metabolites, we developed a quantitative LC/MS assay for one of these free glycans in order to perform longitudinal analysis. The Sandhoff cats showed significant disease-related increases in this glycan in brain and in other matrices including urine which may provide a useful clinical tool for measuring disease severity and therapeutic efficacy. Finally, we observed age-dependent increasing accumulation for a number of analytes, especially in Sandhoff cats where glycosphingolipid, phospholipid, and glycan levels showed incremental increases at later time points without signs of peaking. This large animal natural history study for Sandhoff and Tay-Sachs is the first of its kind, providing insight into disease progression at the biochemical level. This report may help in the development and testing of new therapies to treat these disorders.
β-己糖胺酶是一种负责降解神经节苷脂、聚糖和其他含有β-linked 己糖胺的糖缀合物的酶，这些物质进入溶酶体。GM2 神经节苷脂贮积症，如泰萨二氏症和桑德霍夫病，是溶酶体贮积症，其特征是β-己糖胺酶缺乏，随后其底物代谢物在溶酶体中积累。这两种疾病导致儿童神经退行性变和早期死亡。这两种疾病的一个显著区别是桑德霍夫病中可溶性寡糖代谢物的积累，这些代谢物来源于 N-和 O-连接的聚糖。在本文中，我们描述了我们对沙多夫病猫模型和泰萨二氏症绵羊模型进行的纵向生化研究的结果，以研究 GM2/GA2 神经节苷脂、磷脂病的二级生物标志物、双-(单酰基甘油基)-磷酸酯和可溶性糖代谢物在这两种动物模型的组织和体液样本中的积累。虽然沙多夫病猫和泰萨二氏症绵羊与年龄匹配的未受影响的对照组相比，都积累了大量的 GM2 和 GA2 神经节苷脂，但沙多夫病猫的疾病更为严重，其枕叶中积累的神经节苷脂比泰萨二氏症绵羊多。为了监测糖代谢物，我们开发了一种定量 LC/MS 测定法，用于测定其中一种游离糖的含量，以便进行纵向分析。沙多夫病猫的脑和其他基质（包括尿液）中的这种糖出现了与疾病相关的显著增加，这可能为测量疾病严重程度和治疗效果提供了一种有用的临床工具。最后，我们观察到许多分析物的年龄依赖性积累增加，尤其是在沙多夫病猫中，神经鞘脂、磷脂和聚糖水平在后期时间点呈递增趋势，没有达到峰值的迹象。这项针对沙多夫病和泰萨二氏症的大型动物自然史研究是首例，为了解生化水平的疾病进展提供了线索。本报告可能有助于开发和测试治疗这些疾病的新疗法。
