Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
Neuroscience. 2019 Nov 10;420:41-49. doi: 10.1016/j.neuroscience.2019.03.057. Epub 2019 Apr 4.
Successive fusion events between transport vesicles and their target membranes mediate trafficking of secreted, membrane- and organelle-localised proteins. During the initial steps of this process, termed the secretory pathway, COPII vesicles bud from the endoplasmic reticulum (ER) and fuse with the cis-Golgi membrane, thus depositing their cargo. This fusion step is driven by a quartet of SNARE proteins that includes the cis-Golgi t-SNARE Membrin, encoded by the GOSR2 gene. Mis-sense mutations in GOSR2 result in Progressive Myoclonus Epilepsy (PME), a severe neurological disorder characterised by ataxia, myoclonus and seizures in the absence of significant cognitive impairment. However, given the ubiquitous and essential function of ER-to-Golgi transport, why GOSR2 mutations cause neurological dysfunction and not lethality or a broader range of developmental defects has remained an enigma. Here we highlight new work that has shed light on this issue and incorporate insights into canonical and non-canonical secretory trafficking pathways in neurons to speculate as to the cellular and molecular mechanisms underlying GOSR2 PME. This article is part of a Special Issue entitled: SNARE proteins: a long journey of science in brain physiology and pathology: from molecular.
连续的运输囊泡与其靶膜之间的融合事件介导了分泌的、膜结合的和细胞器定位的蛋白质的运输。在这个过程的初始步骤中，被称为分泌途径，COPII 囊泡从内质网（ER）出芽并与顺式高尔基体膜融合，从而将其货物沉积下来。这个融合步骤是由一个四重 SNARE 蛋白驱动的，其中包括顺式高尔基体 t-SNARE Membrin，由 GOSR2 基因编码。GOSR2 中的错义突变导致进行性肌阵挛性癫痫（PME），这是一种严重的神经疾病，其特征是在没有明显认知障碍的情况下出现共济失调、肌阵挛和癫痫发作。然而，鉴于 ER 到高尔基体运输的普遍和必需功能，为什么 GOSR2 突变会导致神经功能障碍而不是致死或更广泛的发育缺陷仍然是一个谜。在这里，我们强调了一些新的工作，这些工作阐明了这个问题，并将经典和非经典的分泌运输途径的见解纳入到神经元中，以推测 GOSR2 PME 的细胞和分子机制。本文是一个特刊的一部分，主题是：SNARE 蛋白：脑生理学和病理学中的科学之旅：从分子角度。
