Neuronal activity induces glucosylceramide that is secreted via exosomes for lysosomal degradation in glia.

Recessive variants in cause Gaucher disease, a prevalent form of lysosome storage disease. encodes a lysosomal enzyme that hydrolyzes glucosylceramide (GlcCer) into glucose and ceramide. Its loss causes lysosomal dysfunction and increased levels of GlcCer. We generated a null allele of the ortholog by inserting the using CRISPR-Cas9. Here, we show that is expressed in glia but not in neurons. Glial-specific knockdown recapitulates the defects found in mutants, and these can be rescued by glial expression of human . We show that GlcCer is synthesized upon neuronal activity, and it is transported from neurons to glia through exosomes. Furthermore, we found that glial TGF-β/BMP induces the transfer of GlcCer from neurons to glia and that the White protein, an ABCG transporter, promotes GlcCer trafficking to glial lysosomes for degradation.