Internal medicine

Receptor

Pathological

Glycolipid

Leukodystrophy

Ceramide

Sphingosine

Disease

Sphingolipid

Biology

Apoptosis

Galactose

Krabbe disease

Biochemistry

Medicine

Proceedings of the National Academy of Sciences

Significance This study identifies the source of the toxic glycolipid, galactosylsphingosine (psychosine), which accumulates in the inherited demyelinating disorder, Krabbe disease. It was suggested that psychosine was produced anabolically by the addition of galactose to sphingosine. We show here instead that psychosine is derived from the catabolic deacylation of galactosylceramide by the lysososomal enzyme acid ceramidase. These findings allow us to test and confirm the ∼45-y-old “psychosine hypothesis,” which states that psychosine causes the pathological and clinical signs of Krabbe disease. Finally, these data suggest that acid ceramidase could be a substrate reduction target for treating Krabbe disease. We show that pharmacological inhibition of acid ceramidase significantly increases the life span of the twitcher mouse, an authentic murine model of Krabbe disease.

Genetic ablation of acid ceramidase in Krabbe disease confirms the psychosine hypothesis and identifies a new therapeutic target