Abstract
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.
Highlights
Fabry disease (FD, Online Mendelian Inheritance in Man (OMIM) 301500) is one of more than 40 lysosomal storage diseases (LSD) [1]
The aim of the present study was to identify candidate small molecules able to increase mutant α-Gal A activity in patient-derived fibroblasts, and to provide a deeper understanding of the mechanisms initiated by the proteostasis regulators (PRs) that may be responsible for the effect on α-Gal A
We have demonstrated the efficacy of the PRs MG132, BTZ, Clasto-Lactacystin β-lactone (CLC) and Eeyarestatin I (EerI) as potential drugs for FD by increasing enzyme activity of variant forms of the α-Gal A
Summary
Fabry disease (FD, OMIM 301500) is one of more than 40 lysosomal storage diseases (LSD) [1]. FD is caused by mutations in the X-linked gene encoding the lysosomal enzyme α-Galactosidase A (gene symbol: GLA, protein: α-Gal A) leading to absent or diminished activity of the enzyme [3]. Many missense variants of the GLA gene lead to impaired protein processing within the endoplasmic reticulum (ER) and an altered conformation that results in ER retention and premature ER-associated degradation (ERAD) [4]. Deficient activity of α-Gal A, in turn, causes progressive accumulation of Globotriaosylceramide (Gb3). The measurement of lyso-Gb3 in plasma and whole blood is considered of diagnostic as well as of prognostic value for the assessment of the clinical outcome of GLA mutations [5,6,7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
