biostudies-literatureKreher CNational Institute of Neurological Disorders and StrokeEuropean Leukodystrophy Associatione3001661https://www.ebi.ac.uk/biostudies/studies/S-EPMC9255775biostudies-literatureUnknown20(7)Krabbe disease is caused by a deficiency of the lysosomal galactosylceramidase (GALC) enzyme, which results in the accumulation of galactosylceramide (GalCer) and psychosine. In Krabbe disease, the brunt of demyelination and neurodegeneration is believed to result from the dysfunction of myelinating glia. Recent studies have shown that neuronal axons are both structurally and functionally compromised in Krabbe disease, even before demyelination, suggesting a possible neuron-autonomous role of GALC. Using a novel neuron-specific Galc knockout (CKO) model, we show that neuronal Galc deletion is sufficient to cause growth and motor coordination defects and inflammatory gliosis in mice. Furthermore, psychosine accumulates significantly in the nervous system of neuron-specific Galc-CKO. ConfocaPLoS biologyNeuron-specific ablation of the Krabbe disease gene galactosylceramidase in mice results in neurodegeneration.PMC9255775NS106023NS112327ELA-201802314NS111715NS090835Favret JWeinstock NIShin DHong XGelb MHFeltri MLKreher CMaulik MWrabetz LfalseNeuron-specific ablation of the Krabbe disease gene galactosylceramidase in mice results in neurodegeneration.Krabbe disease is caused by a deficiency of the lysosomal galactosylceramidase (GALC) enzyme, which results in the accumulation of galactosylceramide (GalCer) and psychosine. In Krabbe disease, the brunt of demyelination and neurodegeneration is believed to result from the dysfunction of myelinating glia. Recent studies have shown that neuronal axons are both structurally and functionally compromised in Krabbe disease, even before demyelination, suggesting a possible neuron-autonomous role of GALC. Using a novel neuron-specific Galc knockout (CKO) model, we show that neuronal Galc deletion is sufficient to cause growth and motor coordination defects and inflammatory gliosis in mice. Furthermore, psychosine accumulates significantly in the nervous system of neuron-specific Galc-CKO. Confoca2022-01-01T00:00:00Z2022 Jul2025-04-20T01:03:04.754Z2022-07-23T10:25:42.982ZS-EPMC92557753578933110.1371/journal.pbio.3001661