Chemical chaperones improve transport and enhance stability of mutant α-glucosidases in glycogen storage disease type II

Glycogen storage disease type 11 (GSDII; Pompe disease or acid maltase deficiency) is an autosomal recessive disorder caused by lysosomal acid alpha-glucosidase (A alpha Glu) deficiency and manifests predominantly as skeletal muscle weakness. Defects in post-translational modification and transport of mutant A alpha Glu species are frequently encountered and may potentially be corrected with chaperone-mediated therapy. In the present study, we have tested this hypothesis by using deoxynojirimycin and derivatives as chemical chaperones to correct the A alpha Glu deficiency in cultured fibroblasts from patients with GSDII. Four mutant phenotypes were chosen: Y455F/-Y455F, P545L/P545L, 525del/R600C and D645E/R854X. In case of Y455F/Y455F and P545L/P545L, N-(n-butyl)deoxynojirimycin (NB-DNJ) restored the transport, maturation and activity of AaGlu in a dose dependent manner, while it had no effect on the reference enzyme beta-hexosaminidase. NB-DNJ promoted export from the endoplasmic reticulum (ER) to the lysosomes and stabilized the activity of mutant A alpha Glu species, Y455F and P545L, inside the lysosomes. In long-term culture, the AaGlu activity in the fibroblasts from the patients with mutant phenotypes, Y455F/Y455F and P545L/P545L, increased up to 14.0- and 7.9-fold, respectively, in the presence of 10 mu mol/L NB-DNJ. However, the effect of NB-DNJ on Y455F/Y455F subsided quickly after removal of the compound. We conclude that NB-DNJ acts in low concentration as chemical chaperone for certain mutant forms of AaGlu that are trapped in the ER, poorly transported or labile in the lysosomal environment. Chemical chaperone therapy could create new perspectives for therapeutic intervention in GSDII. (c) 2006 Elsevier Inc. All rights reserved.