Proteostasis regulators modulate proteasomal activity and gene expression to attenuate multiple phenotypes in Fabry disease

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.

Pharmacological Chaperones: A Therapeutic Approach for Diseases Caused by Destabilizing Missense Mutations

“…The first molecule activates the heat shock protein response in various cell types [96] and inhibits proteasome [97], while the latter binds and stabilizes specific mutants of lysosomal acid glucosylceramidase which are responsible for Gaucher disease [98]. A similar approach with proteostasis regulators was tested with Fabry disease [99].…”

Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators

“…Large-scale genomics analysis in models of protein conformational disorders (a term that includes disorders associated with both loss-of-function and gain-of-function instability) has revealed that natural genetic variation may have an important modulatory effect on the phenotype of the disease [ 164 ]. Genetic variation in components of the proteostasis network may thus explain the variations in the penetrance and severity of the disease, and the noticeable deviations of the genotype–phenotype correlations that characterise a complex trait disorder, such as Fabry disease [ 165 ], an attribute that recently has also been associated with AIP [ 13 , 139 ]. This understanding suggests that strategies to restore proteostasis, by either enhancing the folding capacity of the proteostasis network, or modulating the degradation of the incorrectly folded proteins, may represent novel therapeutic strategies for conformational diseases [ 166 ].…”

“…This understanding suggests that strategies to restore proteostasis, by either enhancing the folding capacity of the proteostasis network, or modulating the degradation of the incorrectly folded proteins, may represent novel therapeutic strategies for conformational diseases [ 166 ]. Target-specific pharmacological chaperones are alternative possibilities (see below) and these approaches have often been applied in combination [ 165 ].…”

“…The use of either small molecules (e.g., celastrol) or biologics (e.g., siRNA) that enhance the capacity of the proteostasis network in the relevant cellular compartments, has shown promising results in the case of lysosomal storage disorders, such as Gaucher’s disease, as well as for cystic fibrosis caused by ΔF508 CFTR [ 165 , 167 ]. To our knowledge, studies with these types of proteostatic regulators have not been reported for AIP.…”

Misfolding of Lysosomal α-Galactosidase a in a Fly Model and Its Alleviation by the Pharmacological Chaperone Migalastat

“…Migalastat is an analogue of α-Gal A substrate that binds to the active site of the enzyme [ 30 , 31 ]. Treatment with migalastat was shown to increase enzyme activity in cell culture and in mice expressing amenable mutations [ 32 , 33 , 34 , 35 , 36 , 37 ].…”