Fabry disease is caused by deficient activity of α-galactosidase A-an enzyme that hydrolyses the terminal α-galactosyl moieties from glycolipids and glycoproteins--and subsequent accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3) and galabiosylceramide. However, there is no known link between these compounds and disease severity. In this study, we compared Gb3 isoforms (various fatty acids) and lyso-Gb3 analogs (various sphingosine modifications) in two strains of Fabry disease mouse models: a pure C57BL/6 (B6) background or a B6/129 mixed background, with the latter exhibiting more prominent cardiac and renal hypertrophy and thermosensation deficits. Total Gb3 and lyso-Gb3 levels in the heart, kidney and dorsal root ganglion (DRG) were similar in two strains. However, levels of the C20-fatty acid isoform of Gb3 and particular lyso-Gb3 analogs (+18, +34) were significantly higher in Fabry-B6/129 heart tissue when compared to Fabry-B6. By contrast, there was no difference in Gb3 and lyso-Gb3 isoforms/analogs in the kidneys and DRG between two strains. Furthermore, using immunohistochemistry, we found that Gb3 massively accumulated in DRG mechanoreceptors, a sensory neuron subpopulation with preserved function in Fabry disease. However, Gb3 accumulation was not observed in non-peptidergic nociceptors, the disease-relevant subpopulation that has remarkably increased isolectin-B4 (the marker of non-peptidergic nociceptors) binding and enlarged cell size. These findings suggest that specific species of Gb3 or lyso-Gb3 may play major roles in the pathogenesis of Fabry disease, and that Gb3 and lyso-Gb3 are not responsible for the pathology in all tissues or cell types.

中文翻译：

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评估鞘糖脂在法布里病小鼠模型表型严重程度中的作用。

法布里病是由 α-半乳糖苷酶 A 的活性缺陷引起的 然而，这些化合物与疾病严重程度之间没有已知的联系。在这项研究中，我们比较了两种法布里病小鼠模型中的 Gb3 同种型（各种脂肪酸）和溶血 Gb3 类似物（各种鞘氨醇修饰）：纯 C57BL/6 (B6) 背景或 B6/129 混合背景，与后者表现出更突出的心脏和肾脏肥大和热感觉缺陷。心脏、肾脏和背根神经节 (DRG) 中的总 Gb3 和溶血 Gb3 水平在两种菌株中相似。然而，与 Fabry-B6 相比，Fabry-B6/129 心脏组织中 Gb3 的 C20-脂肪酸异构体和特定溶血-Gb3 类似物（+18、+34）的水平显着更高。相比之下，两种菌株之间的肾脏和 DRG 中的 Gb3 和溶血 Gb3 同种型/类似物没有差异。此外，使用免疫组织化学，我们发现 Gb3 在 DRG 机械感受器中大量积累，DRG 机械感受器是一种在法布里病中功能保留的感觉神经元亚群。然而，在非肽能伤害感受器中未观察到 Gb3 积累，该疾病相关亚群显着增加了同种凝集素-B4（非肽能伤害感受器的标志物）结合并扩大了细胞大小。这些发现表明特定种类的 Gb3 或 lyso-Gb3 可能在法布里病的发病机制中起主要作用，