ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2010
Molecular characterization of mutations that cause globoid cell leukodystrophy and pharmacological rescue using small molecule chemical chaperones.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 1 of them a synthesis that pooled it.
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Who cites it
52 citing papers in PubMed, 1 synthesis or guideline pooled it, 90 citations in OpenAlex.
- Emerging links between pediatric lysosomal storage diseases and adult parkinsonism.Movement disorders : official journal of the Movement Disorder Society · 2019Pooled it
- Molecular Dynamics Simulations of 4Computational and structural biotechnology journal · 2026Article
- Genetic and Clinical Characteristics of Chinese Adult Patients With Krabbe Disease.CNS neuroscience & therapeutics · 2025Article
- Molecular Characterization of the GALC Mutation Thr112Ala Causing Krabbe Disease.International journal of molecular sciences · 2025Article
- Lysosomal TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism.Communications biology · 2024Article
- Perinatal loss of galactosylceramidase in both oligodendrocytes and microglia is crucial for the pathogenesis of Krabbe disease in mice.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Preclinical studies in Krabbe disease: A model for the investigation of novel combination therapies for lysosomal storage diseases.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Review
- Galactosylceramidase deficiency and pathological abnormalities in cerebral white matter of Krabbe disease.Neurobiology of disease · 2022Article
- Neuron-specific ablation of the Krabbe disease gene galactosylceramidase in mice results in neurodegeneration.PLoS biology · 2022Article
- CRISPR-Cas9 Knock-In of T513M and G41S Mutations in the Murine β-Galactosyl-Ceramidase Gene Re-capitulates Early-Onset and Adult-Onset Forms of Krabbe Disease.Frontiers in molecular neuroscience · 2022Article
- Emerging cellular themes in leukodystrophies.Frontiers in cell and developmental biology · 2022Review
- Human iPSC-based neurodevelopmental models of globoid cell leukodystrophy uncover patient- and cell type-specific disease phenotypes.Stem cell reports · 2021Article
- Two Cases of Female Chinese Adult-Onset Krabbe Disease with One Novel Mutation and a Review of Literature.Journal of molecular neuroscience : MN · 2021Review
- Krabbe Disease: Prospects of Finding a Cure Using AAV Gene Therapy.Frontiers in medicine · 2021Review
- Brainstem development requires galactosylceramidase and is critical for pathogenesis in a model of Krabbe disease.Nature communications · 2020Article
- Second-Generation Pharmacological Chaperones: Beyond Inhibitors.Molecules (Basel, Switzerland) · 2020Review
- Macrophages Expressing GALC Improve Peripheral Krabbe Disease by a Mechanism Independent of Cross-Correction.Neuron · 2020Article
- Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses.International journal of molecular sciences · 2019Review
- An Engineered Galactosylceramidase Construct Improves AAV Gene Therapy for Krabbe Disease in Twitcher Mice.Human gene therapy · 2019Article
- X-Ray Crystallography in Structure-Function Characterization of Therapeutic Enzymes.Advances in experimental medicine and biology · 2019Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Globoid cell leukodystrophy (GLD) (Krabbe disease) is an autosomal recessive, degenerative, lysosomal storage disease caused by a severe loss of galactocerebrosidase (GALC) enzymatic activity. Of the >70 disease-causing mutations in the GALC gene, most are located outside of the catalytic domain of the enzyme. To determine how GALC mutations impair enzymatic activity, we investigated the impact of multiple disease-causing mutations on GALC processing, localization, and enzymatic activity. Studies in mammalian cells revealed dramatic decreases in GALC activity and a lack of appropriate protein processing into an N-terminal GALC fragment for each of the mutants examined. Consistent with this, we observed significantly less GALC localized to the lysosome and impairment in either the secretion or reuptake of mutant GALC. Notably, the D528N mutation was found to induce hyperglycosylation and protein misfolding. Reversal of these conditions resulted in an increase in proper processing and GALC activity, suggesting that glycosylation may play a critical role in the disease process in patients with this mutation. Recent studies have shown that enzyme inhibitors can sometimes "chaperone" misfolded polypeptides to their appropriate target organelle, bypassing the normal cellular quality control machinery and resulting in enhanced activity. To determine whether this may also work for GLD, we examined the effect of alpha-lobeline, an inhibitor of GALC, on D528N mutant cells. After treatment, GALC activity was significantly increased. This study suggests that mutations in GALC can cause GLD by impairing protein processing and/or folding and that pharmacological chaperones may be potential therapeutic agents for patients carrying certain mutations.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.