North Sea Progressive Myoclonus Epilepsy is Exacerbated by Heat, A Phenotype Primarily Associated with Affected Glia. (15th December 2019)

• Record Type: Journal Article
• Authors: Lambrechts, Roald A.; Polet, Sjoukje S.; Hernandez-Pichardo, Alejandra; van Ninhuys, Lisa; Gorter, Jenke A.; Grzeschik, Nicola A.; de Koning-Tijssen, Marina A.J.; de Koning, Tom J.; Sibon, Ody C.M.
• Is Part Of: Neuroscience. Volume 423(2019)
• Page Start: 1
• Page End: 11
• Publication Date: 2019-12-15
• Subjects: myoclonic epilepsy -- childhood onset -- GOSR2 -- glia; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2019.10.035
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: North Sea progressive myoclonus epilepsy (NS-PME), a disease caused by mutations in the GOSR2 gene, is exacerbated by heat. Consistently, a Drosophila fruitfly model for NS-PME shows heat-induced seizure-like behavior. Membrin, the Drosophila orthologue of GOSR2, is required in glia, but not in neurons to prevent heat-induced seizures. Sodium barbital treatment to NS-PME flies decreased heat-induced seizures. The fly model can be used to understand the pathophysiology of NS-PME and to identify treatment strategies. Abstract: Progressive myoclonic epilepsies (PMEs) comprise a group of rare disorders of different genetic aetiologies, leading to childhood-onset myoclonus, myoclonic seizures and subsequent neurological decline. One of the genetic causes for PME, a mutation in the gene coding for Golgi SNAP receptor 2 ( GOSR2 ), gives rise to a PME-subtype prevalent in Northern Europe and hence referred to as North Sea Progressive Myoclonic Epilepsy (NS-PME). Treatment for NS-PME, as for all PME subtypes, is symptomatic; the pathophysiology of NS-PME is currently unknown, precluding targeted therapy. Here, we investigated the pathophysiology of NS-PME. By means of chart review in combination with interviews with patients ( n = 14), we found heat to be an exacerbating factor for a majority of NS-PME patients (86%). To substantiate these findings, we designed a NS-PME Drosophila melanogaster model. Downregulation of the Drosophila GOSR2-orthologue Membrin leads to heat-induced seizure-like behaviour. Specific downregulation of GOSR2/Membrin in glia but not in neuronal cells resulted in a similar phenotype, which was progressive as the flies aged and was partially responsive to treatment with sodium barbital. Our data suggest a role for GOSR2 in glia in the pathophysiology of NS-PME.