Transcriptomic and proteomic profiling of glial versus neuronal Dube3a overexpression reveals common molecular...

Epilepsy affects millions of individuals worldwide and many cases are pharmacoresistant. Duplication 15q syndrome (Dup15q) is a genetic disorder caused by duplications of the 15q11.2-q13.1 region. Phenotypes include a high rate of pharmacoresistant epilepsy. We developed a Dup15q model in Drosophila melanogaster that recapitulates seizures in Dup15q by over-expressing fly Dube3a or human UBE3A in glial cells, but not neurons, implicating glia in the Dup15q epilepsy phenotype. We compared Dube3a overexpression in glia (repo>Dube3a) versus neurons (elav>Dube3a) using transcriptomics and proteomics of whole fly head extracts. We identified 851 transcripts differentially regulated in repo>Dube3a, including an upregulation of glutathione S-transferase (GST) genes that occurred cell autonomously within glial cells. We reliably measured approximately 2,500 proteins by proteomics, most of which were also quantified at the transcript level. Combined transcriptomic and proteomic analysis revealed an enrichment of 21 synaptic transmission genes downregulated at the transcript and protein in repo>Dube3a indicating synaptic proteins change in a cell non-autonomous manner in repo>Dube3a flies. We identified 6 additional glia originating bang-sensitive seizure lines and found upregulation of GSTs in 4 out of these 6 lines. These data suggest GST upregulation is common among gliopathic seizures and may ultimately provide insight for treating epilepsy.