22 Oral - Neurodevelopment I
Thursday April 07, 6:00 PM - 6:15 PM

Authors:
Liping Wang ^{1, 4} ; Guang Lin ^{2, 4}; Zhongyuan Zuo ^{2, 4}; Hugo Bellen ^{1, 2, 3, 4}

Affiliations:
1) Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.; 2) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.; 3) Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.; 4) Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.

Keywords:
k. glia; b. metabolism

Autosomal recessive variants in GBA1 cause Gaucher disease (GD), the most prevalent form of lysosome storage disease. GBA1 encodes a lysosomal enzyme that hydrolyses glucosylceramide (GlcCer) into glucose and ceramide. Loss of GBA1 leads to increased levels of GlcCer which causes lysosomal dysfunction. We generated a Gba1b null allele (Gba1b^T2A-Gal4) using CRISPR technology. We show that Gba1b is specifically expressed in glia and not in neurons at all stages of development as well as in adults. Loss of Gba1b causes a significant reduction in lifespan and a progressive activity-dependent loss of synaptic activity of neurons, which is rescued by glial specific expression of human GBA1. Moreover, glial but not neuronal specific knockdown of Gba1b recapitulates the defects found in Gba1b mutants, indicating that Gba1b is necessary and sufficient in glia to support neuronal function. We show that GlcCer is synthesized upon neuronal activity and that it is transported from neurons to glia through exosomes. In the absence of Gba1b, the glial cells accumulate GlcCer which in turn causes vacuolization and the demise of glia and is followed by neuronal death. The transfer of GlcCer from neurons to glia is induced by a factor secreted by glia. We identified this factor as a BMP ligand, TGF-β, for vertebrate cells. Finally, we show that the White protein, an ABCG transporter, plays an important role in pigment glia and that it modulates GlcCer trafficking to the glial lysosome for degradation by Gba1b through the endolysosomal pathway. Based on our observations the White protein is involved in the degradation of GlcCer in parallel with Gba1b.