Lactosylceramide as a novel target for Substrate Reduction Therapy in Krabbe disease

Krabbe Disease (KD), also known as Globoid Cell Leukodystrophy, is a rare genetic disorder that affects the brain and nervous system. It is caused by mutations in a gene called GALC, which leads to the loss of an important lysosomal enzyme called β-galactosylceramidase. Without this enzyme, different sphingolipids accumulate in the brain, damaging the cells that produce myelin—the protective layer around nerves—and causing severe neurodegeneration, especially in infants.

Until now, most research has focused on a toxic molecule called psychosine, believed to be the main cause of this damage. However, new findings suggest that another substance called lactosylceramide (LacCer), which also accumulates when the GALC enzyme is missing, might play a significant role in the disease. LacCer is known to trigger inflammation in the brain and is found in high amounts in the brains of patients and animal models of KD—even in cases where psychosine is not elevated. This project will explore whether LacCer contributes to the damage seen in KD, especially how it affects the cells responsible for forming myelin (called oligodendrocytes).

The ultimate goal is to determine if LacCer can be targeted by new treatments to slow or stop the disease. Because current treatments for Krabbe Disease—like stem cell transplants—are only effective before symptoms appear, this research could lead to new therapies that work even after the disease has begun. By uncovering a previously overlooked disease mechanism, this project offers a new direction for treating KD and gives hope to patients and families affected by this devastating disorder.