Misfolding of lysosomal α-galactosidase a in a fly model and its alleviation by the pharmacological chaperone migalastat

Hila Braunstein, Maria Papazian, Gali Maor, Jan Lukas, Arndt Rolfs, Mia Horowitz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Fabry disease, an X-linked recessive lysosomal disease, results from mutations in the GLA gene encoding lysosomal α-galactosidase A (α-Gal A). Due to these mutations, there is accumulation of globotriaosylceramide (GL-3) in plasma and in a wide range of cells throughout the body. Like other lysosomal enzymes, α-Gal A is synthesized on endoplasmic reticulum (ER) bound polyribosomes, and upon entry into the ER it undergoes glycosylation and folding. It was previously suggested that α-Gal A variants are recognized as misfolded in the ER and undergo ER-associated degradation (ERAD). In the present study, we used Drosophila melanogaster to model misfolding of α-Gal A mutants. We did so by creating transgenic flies expressing mutant α-Gal A variants and assessing development of ER stress, activation of the ER stress response and their relief with a known α-Gal A chaperone, migalastat. Our results showed that the A156V and the A285D α-Gal A mutants underwent ER retention, which led to activation of unfolded protein response (UPR) and ERAD. UPR could be alleviated by migalastat. When expressed in the fly’s dopaminergic cells, misfolding of α-Gal A and UPR activation led to death of these cells and to a shorter life span, which could be improved, in a mutation-dependent manner, by migalastat.

Original languageEnglish
Article number7397
Pages (from-to)1-20
Number of pages20
JournalInternational Journal of Molecular Sciences
Issue number19
StatePublished - 1 Oct 2020


  • ERAD 4
  • Fabry disease 1
  • Migalastat 5
  • Misfolding 2
  • UPR 3


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