Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway.
Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway.
Int J Mol Sci. 2022 Dec 26;24(1):358. doi: 10.3390/ijms24010358.
Fabry disease (FD) is an X-linked inborn metabolic disorder due to partial or complete lysosomal α-galactosidase A deficiency. FD is characterized by progressive renal insufficiency and cardio- and cerebrovascular involvement. Restricted access on Gb3-independent tissue injury experimental models has limited the understanding of FD pathophysiology and delayed the development of new therapies. Accumulating glycosphingolipids, mainly Gb3 and lysoGb3, are Fabry specific markers used in clinical follow up. However, recent studies suggest there is a need for additional markers to monitor FD clinical course or response to treatment. We used a -knockout zebrafish (ZF) to investigate alternative biomarkers in Gb3-free-conditions. RNA sequencing was used to identify transcriptomic signatures in kidney tissues discriminating -mutant (M) from wild type (WT) ZF. Gene Ontology (GO) and KEGG pathways analysis showed upregulation of immune system activation and downregulation of oxidative phosphorylation pathways in kidneys from M ZF. In addition, upregulation of the Ca signaling pathway was also detectable in M ZF kidneys. Importantly, disruption of mitochondrial and lysosome-related pathways observed in M ZF was validated by immunohistochemistry. Thus, this ZF model expands the pathophysiological understanding of FD, the Gb3-independent effects of mutations could be used to explore new therapeutic targets for FD.
法布里病（FD）是一种 X 连锁的先天性代谢紊乱，由于溶酶体α-半乳糖苷酶 A 部分或完全缺乏所致。FD 的特征是进行性肾功能不全以及心血管和脑血管受累。由于缺乏 Gb3 非依赖性组织损伤实验模型，限制了对 FD 病理生理学的理解，并延迟了新疗法的开发。积累的糖脂，主要是 Gb3 和溶酶体 Gb3，是 FD 临床随访中使用的特异性标志物。然而，最近的研究表明，需要额外的标志物来监测 FD 的临床过程或对治疗的反应。我们使用 -基因敲除斑马鱼（ZF）在无 Gb3 的条件下研究替代生物标志物。使用 RNA 测序鉴定肾脏组织中区分 -突变型（M）和野生型（WT）ZF 的转录组特征。基因本体论（GO）和 KEGG 途径分析显示，MZF 肾脏中的免疫系统激活途径上调，氧化磷酸化途径下调。此外，还可以在 MZF 肾脏中检测到 Ca 信号通路的上调。重要的是，通过免疫组织化学验证了在 MZF 中观察到的线粒体和溶酶体相关途径的破坏。因此，该 ZF 模型扩展了 FD 的病理生理学理解，突变的 Gb3 非依赖性作用可用于探索 FD 的新治疗靶点。
