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

Recessive variants in GBA1 cause Gaucher disease, a prevalent form of lysosome storage disease. GBA1 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 Drosophila ortholog Gba1b by inserting the Gal4 using CRISPR-Cas9. Here, we show that Gba1b is expressed in glia but not in neurons. Glial-specific knockdown recapitulates the defects found in Gba1b mutants, and these can be rescued by glial expression of human GBA1. 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-beta/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.

Automated summary

Recessive variants in GBA1 can lead to Gaucher disease, a common lysosome storage disease. Using CRISPR-Cas9, we generated a null allele of the Drosophila ortholog Gba1b and found that it is expressed in glia but not in neurons. GlcCer is synthesized upon neuronal activity and transported from neurons to glia through exosomes. Glial TGF-beta/BMP induces GlcCer transfer from neurons to glia, and the White protein promotes GlcCer trafficking to glial lysosomes for degradation.