Schmitt-John Thomas
Neurogenetics, Department of Molecular Biology and Genetics, Aarhus University Aarhus, Denmark ; Tauros-Diagnostik Bielefeld, Germany.
Front Neurosci. 2015 Oct 21;9:381. doi: 10.3389/fnins.2015.00381. eCollection 2015.
The wobbler mouse is an animal model for human motor neuron disease, such as amyotrophic lateral sclerosis (ALS). The spontaneous, recessive wobbler mutation causes degeneration of upper and lower motor neurons leading to progressive muscle weakness with striking similarities to the ALS pathology. The wobbler mutation is a point mutation affecting Vps54, a component of the Golgi-associated retrograde protein (GARP) complex. The GARP complex is a ubiquitously expressed Golgi-localized vesicle tethering complex, tethering endosome-derived vesicles to the trans Golgi network. The wobbler point mutation leads to a destabilization of the Vps54 protein and thereby the whole GARP complex. This effectuates impairments of the retrograde vesicle transport, mis-sorting of Golgi- and endosome localized proteins and on the long run defects in Golgi morphology and function. It is currently largely unknown how the destabilization of the GARP complex interferes with the pathological hallmarks, reported for the wobbler motor neuron degeneration, like neurofilament aggregation, axonal transport defects, hyperexcitability, mitochondrial dysfunction, and how these finally lead to motor neuron death. However, the impairments of the retrograde vesicle transport and the Golgi-function appear to be critical phenomena in the molecular pathology of the wobbler motor neuron disease.
摇摆小鼠是一种用于研究人类运动神经元疾病（如肌萎缩侧索硬化症，ALS）的动物模型。自发的隐性摇摆突变会导致上下运动神经元变性，进而导致进行性肌肉无力，这与ALS病理学有惊人的相似之处。摇摆突变是一种影响Vps54的点突变，Vps54是高尔基体相关逆行蛋白（GARP）复合体的一个组成部分。GARP复合体是一种普遍表达的高尔基体定位的囊泡拴系复合体，将内体来源的囊泡拴系到反式高尔基体网络。摇摆点突变导致Vps54蛋白不稳定，从而使整个GARP复合体不稳定。这导致逆行囊泡运输受损、高尔基体和内体定位蛋白的错误分选，长期来看还会导致高尔基体形态和功能缺陷。目前，很大程度上尚不清楚GARP复合体的不稳定如何干扰摇摆运动神经元变性所报道的病理特征，如神经丝聚集、轴突运输缺陷、过度兴奋、线粒体功能障碍，以及这些最终如何导致运动神经元死亡。然而，逆行囊泡运输和高尔基体功能的损害似乎是摇摆运动神经元疾病分子病理学中的关键现象。
