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

Abstract

Lysosomal galactosylceramidase (GALC) is expressed in all brain cells including oligodendrocytes (OLs), microglia and astrocytes, though the cell-specific function of GALC is largely unknown. Mutations in GALC cause Krabbe disease, a fatal neurological lysosomal storage 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 any 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-KO microglia cocultured with Galc-KO OLs elicits globoid cell formation and the overexpression of osteopontin and MCP-1, both proteins 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.