Issue Information

Front coverKrabbe disease (KD) is an inherited demyelinating disease caused by a genetic deficiency of the lysosomal enzyme galactosylceramide (GalCer) β-galactosidase (GALC). The major substrate for GALC is the myelin lipid GalCer. However, the pathogenesis of KD has long been explained by the accumulation of psychosine, a lyso-derivative of GalCer. TheTwitcher (Twi) mouse is a naturally occurring, genetically, and enzymatically authentic mouse model of KD. Saposin-D (Sap-D) is essential for the degradation of ceramide by acid ceramidase (ACDase) in the lysosome. Watanabe et al. revisited the “pshychosine hypothesis” in KD by characterizing Twi mice lacking Sap-D (Twi/Sap-D KO). Twi/Sap-D KO mice were found to almost completely abolish psychosine accumulation in both the CNS and PNS, however, exhibited comparable demyelination to Twi, especially in the PNS. These results indicate tha t psychosine is mainly produced through the deacylation of GalCer by ACDase with the assistance of Sap-D. The demyelination observed in Twi/Sap-D KO mice may be mediated by a psychosine-independent, Sap-D-dependent mechanism. Neuroinflammation through GalCer-induced activation of Sap-D-deficient mac rophages/microglia may play an important role in the demyelination in Twi/Sap-D KO mice.Image contentRepresentative transmission electron microscopy images of Schwann cells in the sciatic nerve of Twi/Sap-D KO mice without psychosine accumulation. Myelin ovoids and crystalloid inclusions similar...
Source: Journal of Neurochemistry - Category: Neuroscience Tags: ISSUE INFORMATION Source Type: research