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α-Galactosidase aggregation is a determinant of pharmacological chaperone efficacy on Fabry disease mutants

Aleksandra Siekierska1, Greet De Baets, Joke Reumers

  • 1Vrije Universiteit Brussel (VUB), Pleinlaan 2, 1050 Brussels, Belgium.

The Journal of Biological Chemistry
|July 10, 2012
PubMed

Insights

Fabry disease treatment with 1-deoxygalactonojirimycin (DGJ) is limited by protein aggregation. Combining DGJ with aggregation inhibitors may improve outcomes for severe alpha-galactosidase mutants.

Area of Science:

  • Biochemistry
  • Genetics
  • Pharmacology

Background:

  • Fabry disease is a lysosomal storage disorder resulting from deficient alpha-galactosidase activity.
  • Pharmacological chaperones, like 1-deoxygalactonojirimycin (DGJ), aim to stabilize mutant alpha-galactosidase for improved lysosomal delivery.
  • Current DGJ therapy shows limited efficacy, with ~65% of mutants responding in patient fibroblasts, and the reasons for this variability are unclear.

Purpose of the Study:

  • To investigate the structural basis for variable response to DGJ in Fabry disease mutants.
  • To determine the role of protein aggregation in the efficacy of pharmacological chaperone therapy.
  • To develop a predictive model for DGJ response based on mutant properties.

Main Methods:

  • Computational modeling to predict mutant protein stability and aggregation propensity.
  • Cell culture experiments (HeLa cells and patient-derived lymphoblasts) to assess mutant aggregation and DGJ response.
  • Development and validation of a scoring function combining stability and aggregation predictors.

Main Results:

  • Protein aggregation negatively impacts DGJ response, distinguishing aggregation-associated from misfolding-associated loss of function.
  • A scoring function integrating predicted thermodynamic stability and aggregation propensity accurately predicts mutant aggregation in HeLa cells.
  • This predictive model also effectively correlates with DGJ response in patient-derived lymphoblasts, indicating aggregation's importance at endogenous expression levels.

Conclusions:

  • Protein aggregation is a key determinant of chemical chaperone efficacy in Fabry disease.
  • Therapeutic strategies for severe Fabry disease mutants may benefit from combining pharmacological chaperones with aggregation inhibitors.
  • Targeting proteostasis to reduce mutant aggregation could enhance treatment outcomes for Fabry disease.

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