Pathological mechanisms underlying Progressive Myoclonus Epilepsy

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Progressive Myoclonus Epilepsy (PME) is a devastating neurological syndrome linked to mutations in several genes, including the Golgi t-SNARE GOSR2. Patients with GOSR2-PME exhibit three main symptoms: myoclonus (involuntary muscle spasms), ataxia (inability to control body movements) and epileptic seizures. These symptoms begin very early (around 2-6 years old), increase in severity with age and eventually lead to premature mortality, often between ages of 20-40, due to respiratory complications. While certain drugs can limit aspects of the disease (such as seizure frequency), GOSR2-PME is generally drug-resistant and is therefore incurable. Thus, there is an urgent need to acquire a fuller understanding of the cellular alterations that lead to nervous system dysfunction in GOSR2-PME. To help achieve this goal, we have generated a range of new in vivo models of this disorder, utilising the fruit fly, Drosophila melanogaster. Despite several hundred million years of evolutionary divergence, the Drosophila genome contains a single homologue of GOSR2 (membrin) that we have found to be functionally interchangeable with human GOSR2. We have generated mutations in Drosophila membrin that correspond to human PME mutations, and have found that these have profound impacts on Drosophila development, particularly the development of synapses at the neuromuscular junction. We will now take advantage of the extensive genetic toolkit and rapid generation time of Drosophila to uncover the molecular and cellular basis of these effects. Given the evolutionary conservation of GOSR2, we expect our findings to be readily transferable to human patients, and to significantly broaden our understanding of the pathological mechanisms underlying PME.