Spatial and temporal brain biodistribution of neuropathogenic sphingolipids of Krabbe disease.

Glycosphingolipids are essential lipids enriched in the outer leaflet of the plasma membrane, particularly those forming the myelin sheaths. Disorders impacting the glycosphingolipid metabolism cause devastating demyelinating diseases. We extend this observation by investigating the brain topographic pattern of the progressive accumulation of these glycosphingolipids throughout the lifespan of the murine model, correlating with alterations in myelin markers and astrogliosis. The reported IMS approach reveals disturbances in the brain glycosphingolipid spatial distribution and abundance, which is of utmost importance when examining the impact of neurotherapeutics targeting these cytotoxically elevated sphingolipids. Similar approaches can be applied to other sphingolipid-neurodegenerative disorders. The development of a novel imaging mass spectrometry (IMS) method provides key information on the spatial distribution and quantification of pathogenic glycosphingolipids, hexosphingosines, and monohexosylceramides across the brain of the murine model of Krabbe disease, an inherited lysosomal deficiency of galactocerebrosidase, associated with a demyelinating disorder with a broad spectrum of age of onset.