Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) is a neurodegenerative disorder caused by loss-of-function mutations in the cystatin B (CSTB) gene. Progression of the clinical symptoms in EPM1 patients, including stimulus-sensitive myoclonus, tonic-clonic seizures, and ataxia, are well described. However, the cellular dysfunction during the presymptomatic phase that precedes the disease onset is not understood. CSTB deficiency leads to alterations in GABAergic signaling, and causes early neuroinflammation followed by progressive neurodegeneration in brains of a mouse model, manifesting as progressive myoclonus and ataxia. Here, we report the first proteome atlas from cerebellar synaptosomes of presymptomatic Cstb-deficient mice, and propose that early mitochondrial dysfunction is important to the pathogenesis of altered synaptic function in EPM1. A decreased sodium- and chloride dependent GABA transporter 1 (GAT-1) abundance was noted in synaptosomes with CSTB deficiency, but no functional difference was seen between the two genotypes in electrophysiological experiments with pharmacological block of GAT-1. Collectively, our findings provide novel insights into the early onset and pathogenesis of CSTB deficiency, and reveal greater complexity to the molecular pathogenesis of EPM1.

Unverricht-Lundborg型（EPM1）进行性肌阵挛性癫痫是由胱抑素B功能丧失突变引起的神经退行性疾病（CSTB）基因。充分描述了EPM1患者的临床症状进展，包括刺激敏感的肌阵挛，强直性阵挛性癫痫发作和共济失调。但是，尚不清楚在疾病发作之前的症状前阶段的细胞功能障碍。CSTB缺乏会导致GABA能信号的改变，并导致早期神经炎症，随后在小鼠模型的大脑中进行性神经变性，表现为进行性肌阵挛和共济失调。在这里，我们报道了症状前小脑突触小体的第一个蛋白质组图谱科技委员会缺陷小鼠，并提出早期线粒体功能异常对EPM1中突触功能改变的发病机制很重要。在CSTB缺乏的突触小体中，钠和氯依赖的GABA转运蛋白1（GAT-1）的丰度降低了，但是在用GAT-1药理学阻断的电生理实验中，两种基因型之间没有发现功能差异。总的来说，我们的发现为CSTB缺乏的早期发作和发病机理提供了新颖的见解，并揭示了EPM1分子发病机理的更大复杂性。