Deficiency of galactosyl-ceramidase in adult oligodendrocytes worsens disease severity during chronic experimental allergic encephalomyelitis.

Galactosyl-ceramidase (GALC) is a ubiquitous lysosomal enzyme crucial for the correct myelination of the mammalian nervous system during early postnatal development. However, the physiological consequence of GALC deficiency in the adult brain remains unknown. In this study, we found that mice with conditional ablation of GALC activity in post-myelinating oligodendrocytes were lethally sensitized when challenged with chronic experimental allergic encephalomyelitis (EAE), in contrast with the non-lethal dysmyelination observed in Galc-ablated mice without the EAE challenge.

CRISPR-Cas9 Knock-In of T513M and G41S Mutations in the Murine β-Galactosyl-Ceramidase Gene Re-capitulates Early-Onset and Adult-Onset Forms of Krabbe Disease.

Krabbe Disease (KD) is a lysosomal storage disorder characterized by the genetic deficiency of the lysosomal enzyme β-galactosyl-ceramidase (GALC). Deficit or a reduction in the activity of the GALC enzyme has been correlated with the progressive accumulation of the sphingolipid metabolite psychosine, which leads to local disruption in lipid raft architecture, diffuse demyelination, astrogliosis, and globoid cell formation. The mouse, the most used animal model, has a nonsense mutation, which limits the study of how different mutations impact the processing and activity of GALC enzyme.

Lipidomic analysis identifies age-disease-related changes and potential new biomarkers in brain-derived extracellular vesicles from metachromatic leukodystrophy mice.

Background: Recent findings show that extracellular vesicle constituents can exert short- and long-range biological effects on neighboring cells in the brain, opening an exciting avenue for investigation in the field of neurodegenerative diseases. Although it is well documented that extracellular vesicles contain many lipids and are enriched in sphingomyelin, cholesterol, phosphatidylserines and phosphatidylinositols, no reports have addressed the lipidomic profile of brain derived EVs in the context of Metachromatic Leukodystrophy, a lysosomal storage disease with established metabolic alterations in sulfatides.

Methods: In this study, we isolated and characterized the lipid content of brain-derived EVs using the arylsulfatase A knockout mouse as a model of the human condition.

The Pathogenic Sphingolipid Psychosine is Secreted in Extracellular Vesicles in the Brain of a Mouse Model of Krabbe Disease.

Psychosine exerts most of its toxic effects by altering membrane dynamics with increased shedding of extracellular vesicles (EVs). In this study, we discovered that a fraction of psychosine produced in the brain of the Twitcher mouse, a model for Krabbe disease, is associated with secreted EVs. We evaluated the effects of attenuating EV secretion in the Twitcher brain by depleting ceramide production with an inhibitor of neutral sphingomyelinase 2, GW4869.

Synaptic Function and Dysfunction in Lysosomal Storage Diseases.

Lysosomal storage diseases (LSDs) with neurological involvement are inherited genetic diseases of the metabolism characterized by lysosomal dysfunction and the accumulation of undegraded substrates altering glial and neuronal function. Often, patients with neurological manifestations present with damage to the gray and white matter and irreversible neuronal decline. The use of animal models of LSDs has greatly facilitated studying and identifying potential mechanisms of neuronal dysfunction, including alterations in availability and function of synaptic proteins, modifications of membrane structure, deficits in docking, exocytosis, recycling of synaptic vesicles, and inflammation-mediated remodeling of synapses.