ArticleHuman molecular genetics2017
Heterozygote galactocerebrosidase (GALC) mutants have reduced remyelination and impaired myelin debris clearance following demyelinating injury.
Article in Human molecular genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 32 citations in OpenAlex.
- How do different cell populations orchestrate myelin regeneration?Biochemical Society transactions · 2025Review
- Amelioration of Inflammation and Metabolic Blockage in GALC Deficient Mice After Enzyme Replacement Therapy via Extracellular Vesicles.International journal of nanomedicine · 2025Article
- Deficiency of galactosyl-ceramidase in adult oligodendrocytes worsens disease severity during chronic experimental allergic encephalomyelitis.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Consequences of oxygen deprivation on myelination and sex-dependent alterations.Molecular and cellular neurosciences · 2023Review
- Galactosylceramidase deficiency and pathological abnormalities in cerebral white matter of Krabbe disease.Neurobiology of disease · 2022Article
- Baicalin Promotes CNS Remyelination via PPARγ Signal Pathway.Neurology(R) neuroimmunology & neuroinflammation · 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
- Human iPSC-derived astrocytes generated from donors with globoid cell leukodystrophy display phenotypes associated with disease.PloS one · 2022Article
- Review
- The multicellular interplay of microglia in health and disease: lessons from leukodystrophy.Disease models & mechanisms · 2021Review
- Waning efficacy in a long-term AAV-mediated gene therapy study in the murine model of Krabbe disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Article
- A catalog of GWAS fine-mapping efforts in autoimmune disease.American journal of human genetics · 2021Review
- Genetic defects in the sphingolipid degradation pathway and their effects on microglia in neurodegenerative disease.Cellular signalling · 2021Review
- Gene-Based Tests of a Genome-Wide Association Study Dataset Highlight Novel Multiple Sclerosis Risk Genes.Frontiers in neuroscience · 2021Article
- Can early treatment of twitcher mice with high dose AAVrh10-GALC eliminate the need for BMT?BioImpacts : BI · 2021Article
- Macrophages Expressing GALC Improve Peripheral Krabbe Disease by a Mechanism Independent of Cross-Correction.Neuron · 2020Article
- Cell-autonomous expression of the acid hydrolase galactocerebrosidase.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- A New Risk Variant for Multiple Sclerosis at 11q23.3Journal of clinical medicine · 2020Article
- Differential Roles of TREM2+ Microglia in Anterograde and Retrograde Axonal Injury Models.Frontiers in cellular neuroscience · 2020Article
- Dynamic Responses of Microglia in Animal Models of Multiple Sclerosis.Frontiers in cellular neuroscience · 2020Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Genome-wide association studies are identifying multiple genetic risk factors for several diseases, but the functional role of these changes remains mostly unknown. Variants in the galactocerebrosidase (GALC) gene, for example, were identified as a risk factor for Multiple Sclerosis (MS); however, the potential biological relevance of GALC variants to MS remains elusive. We found that heterozygote GALC mutant mice have reduced myelin debris clearance and diminished remyelination after a demyelinating insult. We found no histological or behavioral differences between adult wild-type and GALC +/- animals under normal conditions. Following exposure to the demyelinating agent cuprizone, however, GALC +/- animals had significantly reduced remyelination during recovery. In addition, the microglial phagocytic response and elevation of Trem2, both necessary for clearing damaged myelin, were markedly reduced in GALC +/- animals. These altered responses could be corrected in vitro by treatment with NKH-477, a compound discovered as protective in our previous studies on Krabbe disease, which is caused by mutations in both GALC alleles. Our data are the first to show remyelination defects in individuals with a single mutant GALC allele, suggesting such carriers may have increased vulnerability to myelin damage following injury or disease due to inefficient myelin debris clearance. We thus provide a potential functional link between GALC variants and increased MS susceptibility, particularly due to the failure of remyelination associated with progressive MS. Finally, this work demonstrates that genetic variants identified through genome-wide association studies may contribute significantly to complex diseases, not by driving initial symptoms, but by altering repair mechanisms.
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