DLHex-DGJ, a novel derivative of 1-deoxygalactonojirimycin with pharmacological chaperone activity in human G(M1)-gangliosidosis fibroblasts.

[gm1 gangliosidosis]

G (M 1 )-gangliosidosis (GM 1 ) and Morquio B disease (MBD ) are rare lysosomal storage disorders caused by mutations in the gene GLB 1 . Its main gene product , human acid beta -galactosidase (beta -Gal ) degrades two functionally important molecules , G (M 1 )-ganglioside and keratan sulfate in brain and connective tissues , respectively . While GM 1 is a severe , phenotypically heterogenous neurodegenerative disorder , MBD is a systemic bone disease without effects on the central nervous system . A MBD-specific mutation , p .W 273 L , was shown to produce stable beta -Gal precursors , normally transported and processed to mature , intralysosomal beta -Gal . In accordance with the MBD phenotype , elevated residual activity against G (M 1 )-ganglioside , but strongly reduced affinity towards keratan sulfate was found . Most GM 1 alleles , in contrast , were shown to affect precursor stability and intracellular transport . Specific alleles , p .R 201 C and p .R 201 H result in misfolded , unstable precursor proteins rapidly degraded by endoplasmic reticulum-associated protein degradation (ERAD ). They may therefore be sensitive to stabilization by small molecules which bind at the active site and provide proper conformation . Thus the stabilized protein may escape from ERAD processes , and reach the lysosomes in an active state , as proposed for enzyme enhancement therapy (EET ). This paper demonstrates that a novel iminosugar , DLHex-DGJ , has potent effects as competitive inhibitor of human acid beta -galactosidase in vitro , and describes its effects on activity , protein expression , maturation and intracellular transport in vivo in 13 fibroblasts lines with GLB 1 mutations . Beside p .R 201 C and p .R 201 H , two further alleles , p .C 2 30 R and p .G 438 E , displayed significant sensitivity against DLHex-DGJ , with an increase of catalytic activity , and a normalization of transport and lysosomal processing of beta -Gal precursors .