Pathological mechanisms underlying Progressive Myoclonus Epilepsy

进行性肌阵挛癫痫（PME）是一种破坏性的神经系统综合征，与包括高尔基体t-SNARE GOSR 2在内的几个基因的突变有关。GOSR 2-PME患者表现出三种主要症状：肌阵挛（不随意肌肉痉挛）、共济失调（无法控制身体运动）和癫痫发作。这些症状开始非常早（大约2-6岁），随着年龄的增长而加重，并最终导致过早死亡，通常在20-40岁之间，由于呼吸系统并发症。虽然某些药物可以限制疾病的某些方面（如癫痫发作频率），但GOSR 2-PME通常具有耐药性，因此无法治愈。因此，迫切需要获得一个更全面的了解细胞的变化，导致神经系统功能障碍的GOSR 2-PME。为了帮助实现这一目标，我们已经产生了一系列新的这种疾病的体内模型，利用果蝇，果蝇。尽管有数亿年的进化分歧，果蝇基因组包含一个单一的同源GOSR 2（membrane），我们发现它与人类GOSR 2在功能上可以互换。我们已经在果蝇的记忆中产生了与人类PME突变相对应的突变，并发现这些突变对果蝇的发育有深远的影响，特别是神经肌肉接头处突触的发育。我们现在将利用果蝇广泛的遗传工具包和快速的世代时间来揭示这些效应的分子和细胞基础。鉴于GOSR 2的进化保守性，我们希望我们的研究结果可以很容易地转移到人类患者，并显着扩大我们对PME的病理机制的理解。

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.