Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Fantur, K; Hofer, D; Schitter, G; Steiner, AJ; Pabst, BM; Wrodnigg, TM; Stütz, AE; Paschke, E.
DLHex-DGJ, a novel derivative of 1-deoxygalactonojirimycin with pharmacological chaperone activity in human G(M1)-gangliosidosis fibroblasts.
Mol Genet Metab. 2010; 100(3):262-268
Doi: 10.1016/j.ymgme.2010.03.019
Web of Science
PubMed
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FullText_MUG
- Führende Autor*innen der Med Uni Graz
- Fantur Katrin Medea-Emma
- Paschke Eduard
- Co-Autor*innen der Med Uni Graz
- Hofer Doris
- Pabst Bettina
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- Abstract:
- G(M1)-gangliosidosis (GM1) and Morquio B disease (MBD) are rare lysosomal storage disorders caused by mutations in the gene GLB1. Its main gene product, human acid beta-galactosidase (beta-Gal) degrades two functionally important molecules, G(M1)-ganglioside and keratan sulfate in brain and connective tissues, respectively. While GM1 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.W273L, 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(M1)-ganglioside, but strongly reduced affinity towards keratan sulfate was found. Most GM1 alleles, in contrast, were shown to affect precursor stability and intracellular transport. Specific alleles, p.R201C and p.R201H 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 GLB1 mutations. Beside p.R201C and p.R201H, two further alleles, p.C230R and p.G438E, displayed significant sensitivity against DLHex-DGJ, with an increase of catalytic activity, and a normalization of transport and lysosomal processing of beta-Gal precursors.
- Find related publications in this database (using NLM MeSH Indexing)
- 1-Deoxynojirimycin - analogs and derivatives 1-Deoxynojirimycin - chemistry 1-Deoxynojirimycin - pharmacokinetics 1-Deoxynojirimycin - pharmacology
- Alleles -
- Cell Line -
- Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - pharmacology
- Fibroblasts - drug effects Fibroblasts - metabolism
- Gangliosidosis, GM1 - drug therapy Gangliosidosis, GM1 - genetics Gangliosidosis, GM1 - metabolism
- Humans -
- Molecular Chaperones - chemistry Molecular Chaperones - pharmacokinetics Molecular Chaperones - pharmacology
- Mucopolysaccharidosis IV - drug therapy Mucopolysaccharidosis IV - genetics Mucopolysaccharidosis IV - metabolism
- Mutation -
- beta-Galactosidase - antagonists and inhibitors beta-Galactosidase - genetics beta-Galactosidase - metabolism
- Find related publications in this database (Keywords)
- beta-Galactosidase
- G(M1)-Gangliosidosis
- Morquio B disease
- DLHex-DGJ
- Enzyme enhancement therapy
- Pharmacological chaperone