Department of Biomedicine, Faculty of Medicine, University of Barcelona, Catalonia, Spain; Institut de Neurociències, University of Barcelona, 08036, Catalonia, Spain.
Department of Biomedicine, Faculty of Medicine, University of Barcelona, Catalonia, Spain; Institut de Neurociències, University of Barcelona, 08036, Catalonia, Spain.
Exp Neurol. 2021 Aug;342:113755. doi: 10.1016/j.expneurol.2021.113755. Epub 2021 May 11.
RTP801/REDD1 is a stress-regulated protein whose upregulation is necessary and sufficient to trigger neuronal death in in vitro and in vivo models of Parkinson's and Huntington's diseases and is up regulated in compromised neurons in human postmortem brains of both neurodegenerative disorders. Indeed, in both Parkinson's and Huntington's disease mouse models, RTP801 knockdown alleviates motor-learning deficits.
We investigated the physiological role of RTP801 in neuronal plasticity and we found RTP801 in rat, mouse and human synapses. The absence of RTP801 enhanced excitatory synaptic transmission in both neuronal cultures and brain slices from RTP801 knock-out (KO) mice. Indeed, RTP801 KO mice showed improved motor learning, which correlated with lower spine density but increased basal filopodia and mushroom spines in the motor cortex layer V. This paralleled with higher levels of synaptosomal GluA1 and TrkB receptors in homogenates derived from KO mice motor cortex, proteins that are associated with synaptic strengthening.
Altogether, these results indicate that RTP801 has an important role modulating neuronal plasticity and motor learning. They will help to understand its role in neurodegenerative disorders where RTP801 levels are detrimentally upregulated.
RTP801/REDD1 是一种应激调节蛋白，其上调对于触发帕金森病和亨廷顿病的体外和体内模型中的神经元死亡是必需且充分的，并且在这两种神经退行性疾病的人类尸检大脑中的受损神经元中上调。事实上，在帕金森病和亨廷顿病的小鼠模型中，RTP801 的敲低可减轻运动学习缺陷。
我们研究了 RTP801 在神经元可塑性中的生理作用，发现 RTP801 存在于大鼠、小鼠和人类的突触中。在 RTP801 敲除（KO）小鼠的神经元培养物和脑片中，缺乏 RTP801 增强了兴奋性突触传递。事实上，RTP801 KO 小鼠表现出改善的运动学习，这与较低的棘密度但增加的基底丝状伪足和蘑菇状棘突相关，这些改变发生在运动皮层 V 层。这与 KO 小鼠运动皮层匀浆中突触体 GluA1 和 TrkB 受体的水平升高相一致，这些蛋白与突触增强有关。
总之，这些结果表明 RTP801 在调节神经元可塑性和运动学习方面具有重要作用。它们将有助于了解其在神经退行性疾病中的作用，在这些疾病中 RTP801 的水平被不利地上调。
