Pathological mechanisms underlying Progressive Myoclonus Epilepsy

进行性肌阵挛性癫痫（PME）是一种毁灭性的神经系统综合征，与几种基因突变有关，包括高尔基t-SNARE GOSR2。GOSR2-PME患者表现出三种主要症状：肌阵挛（不随意肌痉挛）、共济失调（无法控制身体运动）和癫痫发作。这些症状很早就开始（大约2-6岁），随着年龄的增长，严重程度会增加，最终由于呼吸系统并发症导致过早死亡，通常在20-40岁之间。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GOSR2-PME通常具有耐药性，因此无法治愈。因此，迫切需要更全面地了解导致GOSR2-PME神经系统功能障碍的细胞改变。为了帮助实现这一目标，我们利用果蝇（Drosophila melanogaster）产生了一系列新的这种疾病的体内模型。尽管存在数亿年的进化差异，但果蝇基因组中包含一个与人类GOSR2在功能上可互换的GOSR2（成员蛋白）同源物。我们已经在果蝇的细胞膜中产生了与人类PME突变相对应的突变，并发现这些突变对果蝇的发育，特别是神经肌肉连接处突触的发育有深远的影响。我们现在将利用果蝇广泛的遗传工具箱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GOSR2的进化保守性，我们希望我们的发现能够很容易地转移到人类患者身上，并显著拓宽我们对PME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.