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.

Lysosomal Functions in Glia Associated with Neurodegeneration.

Lysosomes are cellular organelles that contain various acidic digestive enzymes. Despite their small size, they have multiple functions. Lysosomes remove or recycle unnecessary cell parts. They repair damaged cellular membranes by exocytosis. Lysosomes also sense cellular energy status and transmit signals to the nucleus. Glial cells are non-neuronal cells in the nervous system and have an active role in homeostatic support for neurons. In response to dynamic cues, glia use lysosomal pathways for the secretion and uptake of regulatory molecules, which affect the physiology of neighboring neurons. Therefore, functional aberration of glial lysosomes can trigger neuronal degeneration. Here, we review lysosomal functions in oligodendrocytes, astrocytes, and microglia, with emphasis on neurodegeneration.

Brainstem development requires galactosylceramidase and is critical for pathogenesis in a model of Krabbe disease.

Krabbe disease (KD) is caused by a deficiency of galactosylceramidase (GALC), which induces demyelination and neurodegeneration due to accumulation of cytotoxic psychosine. Hematopoietic stem cell transplantation (HSCT) improves clinical outcomes in KD patients only if delivered pre-symptomatically. Here, we hypothesize that the restricted temporal efficacy of HSCT reflects a requirement for GALC in early brain development. Using a novel Galc floxed allele, we induce ubiquitous GALC ablation (Galc-iKO) at various postnatal timepoints and identify a critical period of vulnerability to GALC ablation between P4-6 in mice. Early Galc-iKO induction causes a worse KD phenotype, higher psychosine levels in the rodent brainstem and spinal cord, and a significantly shorter life-span of the mice. Intriguingly, GALC expression peaks during this critical developmental period in mice. Further analysis of this mouse model reveals a cell autonomous role for GALC in the development and maturation of immature T-box-brain-1 positive brainstem neurons. These data identify a perinatal developmental period, in which neuronal GALC expression influences brainstem development that is critical for KD pathogenesis.