Translational Neurodegeneration Section "Albrecht-Kossel", Department of Neurology, University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany.
Institute for Biostatistics and Informatics in Medicine and Ageing Research, University Medical Center Rostock, 18057 Rostock, Germany.
Biochem J. 2020 Jan 31;477(2):359-380. doi: 10.1042/BCJ20190513.
The lysosomal storage disorder Fabry disease is characterized by a deficiency of the lysosomal enzyme α-Galactosidase A. The observation that missense variants in the encoding GLA gene often lead to structural destabilization, endoplasmic reticulum retention and proteasomal degradation of the misfolded, but otherwise catalytically functional enzyme has resulted in the exploration of alternative therapeutic approaches. In this context, we have investigated proteostasis regulators (PRs) for their potential to increase cellular enzyme activity, and to reduce the disease-specific accumulation of the biomarker globotriaosylsphingosine in patient-derived cell culture. The PRs also acted synergistically with the clinically approved 1-deoxygalactonojirimycine, demonstrating the potential of combination treatment in a therapeutic application. Extensive characterization of the effective PRs revealed inhibition of the proteasome and elevation of GLA gene expression as paramount effects. Further analysis of transcriptional patterns of the PRs exposed a variety of genes involved in proteostasis as potential modulators. We propose that addressing proteostasis is an effective approach to discover new therapeutic targets for diseases involving folding and trafficking-deficient protein mutants.
溶酶体贮积症法布里病的特征是溶酶体酶α-半乳糖苷酶 A 的缺乏。观察到编码 GLA 基因中的错义变异经常导致结构不稳定、内质网滞留和折叠但 otherwise 具有催化功能的酶的蛋白酶体降解，这导致了探索替代治疗方法。在这种情况下，我们研究了蛋白质稳态调节剂（PRs），以了解它们是否具有增加细胞酶活性和减少患者来源的细胞培养物中疾病特异性生物标志物神经酰胺三己糖苷积累的潜力。PRs 还与临床批准的 1-脱氧半乳糖酮基霉素协同作用，证明了联合治疗在治疗应用中的潜力。对有效 PRs 的广泛表征揭示了蛋白酶体的抑制和 GLA 基因表达的升高是最重要的作用。对 PRs 的转录模式的进一步分析揭示了涉及蛋白质稳态的各种基因作为潜在的调节剂。我们提出，解决蛋白质稳态是发现涉及折叠和运输缺陷蛋白突变体的疾病的新治疗靶点的有效方法。
