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Proteostasis regulators modulate proteasomal activity and gene expression to attenuate multiple phenotypes in Fabry
Susanne Seemann1, Mathias Ernst2, Chiara Cimmaruta1,3,4
1Translational Neurodegeneration Section "Albrecht-Kossel", Department of Neurology, University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany.
The Biochemical Journal
|January 4, 2020
Summary
Proteostasis regulators can enhance enzyme activity and reduce disease biomarkers in Fabry disease. Combination therapy with these regulators and existing drugs shows therapeutic potential for protein misfolding disorders.
Area of Science:
- Biochemistry
- Genetics
- Cell Biology
Background:
- Fabry disease is a lysosomal storage disorder caused by alpha-Galactosidase A deficiency.
- Missense variants in the GLA gene lead to enzyme misfolding, ER retention, and degradation, despite retained catalytic function.
Purpose of the Study:
- To investigate proteostasis regulators (PRs) for enhancing cellular enzyme activity in Fabry disease.
- To assess the potential of PRs in reducing disease-specific biomarkers.
- To explore combination therapy with PRs and existing treatments.
Main Methods:
- Utilized patient-derived cell cultures.
- Investigated the effects of various proteostasis regulators.
- Performed extensive characterization of effective PRs, including proteasome inhibition and gene expression analysis.
- Analyzed transcriptional patterns to identify potential modulators.
Main Results:
- Proteostasis regulators increased cellular alpha-Galactosidase A activity.
- PRs reduced the accumulation of globotriaosylsphingosine, a key biomarker.
- PRs demonstrated synergistic effects when combined with 1-deoxygalactonojirimycine.
- Effective PRs inhibited the proteasome and elevated GLA gene expression.
Conclusions:
- Targeting proteostasis is a promising therapeutic strategy for Fabry disease.
- PRs offer a novel approach to manage protein misfolding and trafficking defects.
- Combination therapies hold significant potential for treating proteinopathies.
Keywords:
globotriaosylsphingosinelysosomal enzymeproteasome inhibitorprotein misfoldingtranscriptomicsMore Related Videos
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