III. Department of Medicine and.
Hamburg Center for Kidney Health, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
J Clin Invest. 2023 Jun 1;133(11):e157782. doi: 10.1172/JCI157782.
Current therapies for Fabry disease are based on reversing intracellular accumulation of globotriaosylceramide (Gb3) by enzyme replacement therapy (ERT) or chaperone-mediated stabilization of the defective enzyme, thereby alleviating lysosomal dysfunction. However, their effect in the reversal of end-organ damage, like kidney injury and chronic kidney disease, remains unclear. In this study, ultrastructural analysis of serial human kidney biopsies showed that long-term use of ERT reduced Gb3 accumulation in podocytes but did not reverse podocyte injury. Then, a CRISPR/Cas9-mediated α-galactosidase knockout podocyte cell line confirmed ERT-mediated reversal of Gb3 accumulation without resolution of lysosomal dysfunction. Transcriptome-based connectivity mapping and SILAC-based quantitative proteomics identified α-synuclein (SNCA) accumulation as a key event mediating podocyte injury. Genetic and pharmacological inhibition of SNCA improved lysosomal structure and function in Fabry podocytes, exceeding the benefits of ERT. Together, this work reconceptualizes Fabry-associated cell injury beyond Gb3 accumulation, and introduces SNCA modulation as a potential intervention, especially for patients with Fabry nephropathy.
目前治疗法布雷病的方法是通过酶替代疗法（ERT）或伴侣介导的缺陷酶稳定化来逆转细胞内糖鞘脂（Gb3）的积累，从而缓解溶酶体功能障碍。然而，它们在逆转终末器官损伤（如肾脏损伤和慢性肾脏病）方面的效果仍不清楚。在这项研究中，对一系列人类肾脏活检的超微结构分析表明，长期使用 ERT 可减少足细胞中的 Gb3 积累，但不能逆转足细胞损伤。然后，CRISPR/Cas9 介导的α-半乳糖苷酶敲除足细胞系证实，ERT 介导的 Gb3 积累逆转而溶酶体功能障碍没有得到解决。基于转录组的连接性映射和 SILAC 定量蛋白质组学确定α-突触核蛋白（SNCA）的积累是介导足细胞损伤的关键事件。SNCA 的遗传和药理学抑制改善了 Fabry 足细胞的溶酶体结构和功能，其效果超过了 ERT。总之，这项工作重新概念化了 Fabry 相关细胞损伤超越 Gb3 积累的概念，并引入了 SNCA 调节作为一种潜在的干预措施，特别是对于 Fabry 肾病患者。
