低温与冬眠的对神经的保护作用已经为人熟知，但是其保护作用除了能降低氧耗和能量代谢外，我们对其发挥作用的分子机制并不是十分清楚。最近发表在《自然》的一项研究揭示了其机制可能与蛋白质RBM3有关。
在健康肌体中，突触-神经元间相互联系的基本结构是通过形成与消除而处于动态的变化状态，这是我们常说的可塑性。而在退行性神经病变的病理情况下，突触会减少，从而导致神经元间的联系受到损害。在冬眠动物中，突触会在冬眠期间减少，随着冬眠结束而重新增加，而这些变化伴随着大脑中一种蛋白质—冷休克蛋白RBM3的变化。该现象促使英国莱斯特大学的科学工作者试图寻找它们之间的联系。
Mallucci博士与他的团队在朊病毒（prion）感染的小鼠（海绵状脑组织病变模型）和5XFAD小鼠（一种阿尔茨海默氏病模型）中发现低温可导致突触的丢失和RBM3蛋白的减少，提高RBM3蛋白的表达则可阻止低温导致的突触丧失、防止小鼠出现行为缺陷和神经元的丧失，并延长其生存期。相反，应用基因敲除技术降低RBM3蛋白的表达则起到相反的效果。
该研究将科学工作者对退行性神经病变的认识推进了一大步，可能促使人们寻找一种能够改变RBM3蛋白表达的物质来保护神经元的病变和突触的丢失。 |
原文信息：
RBM3 mediates structural plasticity and protective effects of cooling in neurodegeneration
Nature 518, 236–239 (12 February 2015) doi:10.1038/nature14142
In the healthy adult brain synapses are continuously remodelled through a process of elimination and formation known as structural plasticity1. Reduction in synapse number is a consistent early feature of neurodegenerative diseases2, 3, suggesting deficient compensatory mechanisms. Although much is known about toxic processes leading to synaptic dysfunction and loss in these disorders2, 3, how synaptic regeneration is affected is unknown. In hibernating mammals, cooling induces loss of synaptic contacts, which are reformed on rewarming, a form of structural plasticity4, 5. We have found that similar changes occur in artificially cooled laboratory rodents. Cooling and hibernation also induce a number of cold-shock proteins in the brain, including the RNA binding protein, RBM3 (ref. 6). The relationship of such proteins to structural plasticity is unknown. Here we show that synapse regeneration is impaired in mouse models of neurodegenerative disease, in association with the failure to induce RBM3. In both prion-infected and 5XFAD (Alzheimer-type) mice7, the capacity to regenerate synapses after cooling declined in parallel with the loss of induction of RBM3. Enhanced expression of RBM3 in the hippocampus prevented this deficit and restored the capacity for synapse reassembly after cooling. RBM3 overexpression, achieved either by boosting endogenous levels through hypothermia before the loss of the RBM3 response or by lentiviral delivery, resulted in sustained synaptic protection in 5XFAD mice and throughout the course of prion disease, preventing behavioural deficits and neuronal loss and significantly prolonging survival. In contrast, knockdown of RBM3 exacerbated synapse loss in both models and accelerated disease and prevented the neuroprotective effects of cooling. Thus, deficient synapse regeneration, mediated at least in part by failure of the RBM3 stress response, contributes to synapse loss throughout the course of neurodegenerative disease. The data support enhancing cold-shock pathways as potential protective therapies in neurodegenerative disorders.
原文链接： http://www.nature.com/nature/journal/vaop/ncurrent/full/nature14142.html |
