Neuron-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. 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. Krabbe disease is a demyelinating neurodegenerative disorder caused by a deficiency of the enzyme lysosomal galactosylceramidase (GALC), which results in the accumulation of galactosylceramide and psychosine. This study uses a novel neuron-specific knockout model in the first in vivo attempt to investigate the role of neuronal GALC in neuronal function and the etiology of Krabbe disease. [ABSTRACT FROM AUTHOR]