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Publication : Perinatal loss of galactosylceramidase in both oligodendrocytes and microglia is crucial for the pathogenesis of Krabbe disease in mice.

First Author  Favret J Year  2024
Journal  Mol Ther Volume  32
Issue  7 Pages  2207-2222
PubMed ID  38734898 Mgi Jnum  J:360131
Mgi Id  MGI:7797671 Doi  10.1016/j.ymthe.2024.05.019
Citation  Favret J, et al. (2024) Perinatal loss of galactosylceramidase in both oligodendrocytes and microglia is crucial for the pathogenesis of Krabbe disease in mice. Mol Ther 32(7):2207-2222
abstractText  Lysosomal galactosylceramidase (GALC) is expressed in all brain cells, including oligodendrocytes (OLs), microglia, and astrocytes, although the cell-specific function of GALC is largely unknown. Mutations in GALC cause Krabbe disease (KD), a fatal neurological lysosomal disorder that usually affects infants. To study how Galc ablation in each glial cell type contributes to Krabbe pathogenesis, we used conditional Galc-floxed mice. Here, we found that OL-specific Galc conditional knockout (CKO) in mice results in a phenotype that includes wasting, psychosine accumulation, and neuroinflammation. Microglia- or astrocyte-specific Galc deletion alone in mice did not show specific phenotypes. Interestingly, mice with CKO of Galc from both OLs and microglia have a more severe neuroinflammation with an increase in globoid cell accumulation than OL-specific CKO alone. Moreover, the enhanced phenotype occurred without additional accumulation of psychosine. Further studies revealed that Galc knockout (Galc-KO) microglia cocultured with Galc-KO OLs elicits globoid cell formation and the overexpression of osteopontin and monocyte chemoattractant protein-1, both proteins that are known to recruit immune cells and promote engulfment of debris and damaged cells. We conclude that OLs are the primary cells that initiate KD with an elevated psychosine level and microglia are required for the progression of neuroinflammation in a psychosine-independent manner.
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