MRC Harwell Institute, Harwell Campus, Oxfordshire OX11 0RD, UK.
Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Dis Model Mech. 2019 Feb 22;12(2):dmm036806. doi: 10.1242/dmm.036806.
Loss-of-function mutations in a human AMPA receptor-associated protein, ferric chelate reductase 1-like (FRRS1L), are associated with a devastating neurological condition incorporating choreoathetosis, cognitive deficits and epileptic encephalopathies. Furthermore, evidence from overexpression and studies has implicated FRRS1L in AMPA receptor biogenesis, suggesting that changes in glutamatergic signalling might underlie the disorder. Here, we investigated the neurological and neurobehavioural correlates of the disorder using a mouse null mutant. The study revealed several neurological defects that mirrored those seen in human patients. We established that mice lacking suffered from a broad spectrum of early-onset motor deficits with no progressive, age-related deterioration. Moreover, mice were hyperactive, irrespective of test environment, exhibited working memory deficits and displayed significant sleep fragmentation. Longitudinal electroencephalographic (EEG) recordings also revealed abnormal EEG results in mice. Parallel investigations into disease aetiology identified a specific deficiency in AMPA receptor levels in the brain of mice, while the general levels of several other synaptic components remained unchanged, with no obvious alterations in the number of synapses. Furthermore, we established that deletion results in an increased proportion of immature AMPA receptors, indicated by incomplete glycosylation of GLUA2 (also known as GRIA2) and GLUA4 (also known as GRIA4) AMPA receptor proteins. This incomplete maturation leads to cytoplasmic retention and a reduction of those specific AMPA receptor levels in the postsynaptic membrane. Overall, this study determines, for the first time , how loss of FRRS1L function can affect glutamatergic signalling, and provides mechanistic insight into the development and progression of a human hyperkinetic disorder.This article has an associated First Person interview with the first author of the paper.
功能丧失性突变在人类 AMPA 受体相关蛋白，亚铁螯合还原酶 1 样蛋白（FRRS1L）中，与一种毁灭性的神经疾病有关，包括舞蹈手足徐动症、认知缺陷和癫痫性脑病。此外，过表达和研究证据表明 FRRS1L 参与 AMPA 受体的生物发生，表明谷氨酸能信号的变化可能是这种疾病的基础。在这里，我们使用小鼠 缺失突变体研究了该疾病的神经和神经行为相关性。研究揭示了几种与人类患者相似的神经缺陷。我们确定缺乏 的小鼠患有广泛的早期运动缺陷，没有进行性、与年龄相关的恶化。此外， 小鼠无论在何种测试环境下都异常活跃，表现出工作记忆缺陷，并显示出明显的睡眠碎片化。纵向脑电图（EEG）记录也显示 小鼠的 EEG 结果异常。对疾病病因的平行研究发现， 小鼠大脑中的 AMPA 受体水平存在特定缺陷，而其他几种突触成分的总体水平保持不变，突触数量没有明显变化。此外，我们确定 缺失导致不成熟的 AMPA 受体比例增加，这表明 GLUA2（也称为 GRIA2）和 GLUA4（也称为 GRIA4）AMPA 受体蛋白的不完全糖基化。这种不完全成熟导致细胞质保留和突触后膜中特定 AMPA 受体水平的降低。总的来说，这项研究首次确定了 FRRS1L 功能丧失如何影响谷氨酸能信号，并为人类多动障碍的发展和进展提供了机制上的见解。本文有一篇与论文第一作者的第一人称访谈。
