Neuron-specific ablation of the Krabbe disease gene galactosylceramidase in mice results in neurodegeneration

Conlan Kreher, Jacob Favret, Nadav I. Weinstock, Malabika Maulik, Xinying Hong, Michael H. Gelb, Lawrence Wrabetz, M. Laura Feltri, Daesung Shin

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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 neuronspecific 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. Confocal and electron microscopic analyses show profound neuro-axonal degeneration with a mild effect on myelin structure. Thus, we prove for the first time that neuronal GALC is essential to maintain and protect neuronal function independently of myelin and may directly contribute to the pathogenesis of Krabbe disease.

Original languageEnglish
Article numbere3001661
JournalPLoS Biology
Issue number7
StatePublished - Jul 2022
Externally publishedYes


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