Error-prone protein synthesis recapitulates early symptoms of Alzheimer disease in aging mice

Age-related neurodegenerative diseases (NDDs) and neuronal dysfunction are associated with the aggregation and propagation of specific pathogenic protein species (e.g. alphaBeta, alpha-synuclein, tau). However, whether the disruption of synaptic homeostasis results from protein misfolding per se rather than accumulation of a specific rogue protein is an unexplored question. Here, we show that error-prone translation with its frequent outcome of random protein misfolding is sufficient to recapitulate many early features of NDDs, including proteostasis dysregulation, perturbed Ca2+ signalling, neuronal hyperexcitability, and mitochondrial dysfunction. Mice expressing the ribosomal ambiguity mutation Rps9 D95N exhibited disrupted synaptic homeostasis resulting in abnormal behavioral changes reminiscent of early Alzheimer's disease (AD), such as learning and memory deficits, maladaptive responses to novel stimuli, spontaneous epileptiform discharges, suppressed circadian rhythmicity, and sleep fragmentation. Ectopic hippocampal NPY expression and cerebral glucose hypometabolism (18F-fluorodeoxyglucose PET) were further signs of neuronal hyperexcitability. Collectively, our findings strongly suggest that random protein misfolding may contribute to the pathogenesis of age-related NDDs providing an alternative framework for understanding the initiation of Alzheimer's disease. Transcriptomic profile of total RNA extracted from brain cortex of 7 mutant mice (mutation Rps9 D95N) were compared with the profile of 8 WT littermate control mice. 18 months old female mice were used in the experiment.年龄相关性神经退行性疾病（Age-related neurodegenerative diseases, NDDs）与神经元功能障碍，均与特定致病性蛋白质亚型的聚集与传播密切相关，例如αβ蛋白、α-突触核蛋白、tau蛋白。 然而，突触稳态的破坏究竟源于蛋白质错误折叠本身，而非特定致病性错误折叠蛋白的聚集，这一问题迄今尚未得到探索。 本研究证实，易出错翻译及其频繁引发的随机蛋白质错误折叠，足以复现年龄相关性神经退行性疾病的诸多早期特征，包括蛋白质稳态失调、钙信号通路紊乱、神经元过度兴奋以及线粒体功能障碍。 携带核糖体歧义突变Rps9 D95N的小鼠，其突触稳态遭到破坏，进而出现类似早期阿尔茨海默病（Alzheimer's disease, AD）的异常行为改变，包括学习记忆障碍、对新异刺激的适应不良反应、自发性癫痫样放电、昼夜节律抑制以及睡眠片段化。 海马区异位神经肽Y（Neuropeptide Y, NPY）表达与大脑葡萄糖低代谢（18F-氟脱氧葡萄糖正电子发射断层扫描，18F-fluorodeoxyglucose PET），均为神经元过度兴奋的佐证征象。 综上，本研究结果强烈提示，随机蛋白质错误折叠可能参与年龄相关性神经退行性疾病的发病机制，为理解阿尔茨海默病的起始过程提供了全新的理论框架。 本研究对7只携带Rps9 D95N突变的突变型小鼠大脑皮层提取的总RNA的转录组特征，与8只同窝野生型（wild type, WT）对照小鼠的转录组特征进行了对比。 本实验所用小鼠均为18月龄雌性个体。