Globoid cell leukodystrophy (GLD) is an inherited neurological disorder caused by the deficiency of galactocerebrosidase (GALC) activity resulting in cell death of oligodendrocytes and subsequent demyelination. The death of oligodendrocytes is accompanied by accumulation of psychosine, which is also a substrate for the GALC enzyme. In this report, we investigated the mechanism of the toxic effect of psychosine in a mouse-derived oligodendrocyte progenitor cell line (OLP-II), a precursor to the cell type most affected in GLD. Psychosine caused cytotoxicity in a dose-dependent manner. Lower concentration of psychosine (5 microM) did not significantly reduce OLP-II cell numbers. However, 50 microM psychosine induced up to 45% cell death. These results were confirmed by the Tunel assay, which is a hallmark for the detection of apoptosis. Moreover, psychosine treatment resulted in the activation/cleavage of initiator caspase-8 and -9, and effector caspase-3. These results support a role for psychosine in OLP-II cell death via an apoptotic mechanism, and suggest the involvement of caspases.