Abstract
North Sea Progressive Myoclonus Epilepsy (NS-PME) is a rare genetic disease that presents at an early age with progressive ataxia, myoclonus, and epilepsy. The disease is caused by a mutation in the Golgi SNAP receptor 2 gene (GOSR2). However, the consequences of this genetic defect at the cellular level are still unknown. Using a NS-PME Drosophila melanogaster model, it was previously found that knockdown of membrin, the fruit fly GOSR2 ortholog, in glial cells leads to progressive heat-induced seizure-like behavior in adult flies. Upon close inspection, we found NS-PME flies not only show progressive heat-induced seizures but also disrupted sleep architecture (higher number of shorter sleep bouts). Here we asked what glial cellular consequences could be underlying these phenotypes of membrin knockdown. First, we investigate whether these phenotypes are attributed to specific glial types; we found that these phenotypes were partly reproduced with specific knockdown of membrin in perineurial glia only. Next, we show that Innexin2, a gap junction protein specifically expressed in glia, is affected upon membrin knockdown, with an altered expression pattern and reduced protein levels. Finally, glial overexpression of Innexin2 in the background of glial membrin knockdown strongly ameliorates the heat-induced seizure phenotype, disrupted sleep architecture, as well as Innexin2 expression pattern, corroborating the importance of Innexin2 in maintaining neuronal homeostasis in NS-PME. These findings show that dysregulation of Innexin2 at least partially underlies the phenotypes of membrin knockdown in Drosophila melanogaster and could suggest a similar role of Innexin2-like proteins in the human disease NS-PME.
