RBM3 mediates structural plasticity and protective effects of cooling in neurodegeneration.
RBM3 mediates structural plasticity and protective effects of cooling in neurodegeneration.
复制标题
DOI：
10.1038/nature14142
复制
发表时间：
2015-02-12
期刊：
影响因子：
64.8
通讯作者：
Mallucci, Giovanna R.
中科院分区：
文献类型：
--
作者：
Peretti, Diego;Bastide, Amandine;Radford, Helois;Verity, Nicholas;Molloy, Colin;Martin, Maria Guerra;Moreno, Julie A.;Steinert, Joern R.;Smith, Tim;Dinsdale, David;Willis, Anne E.;Mallucci, Giovanna R.
在健康的成年人大脑中，突触通过一个被称为结构可塑性的消除和形成过程不断重塑。突触数量减少是神经退行性疾病的一个一致的早期特征，表明代偿机制不足。虽然对导致这些疾病中突触功能障碍和丧失的毒性过程了解很多，但突触再生如何受到影响尚不清楚。在冬眠的哺乳动物中，冷却会导致突触接触的丧失，这些突触接触在复温时重新形成，这是一种结构可塑性的形式。我们发现，在人工冷却的实验室啮齿动物中也发生了类似的变化。冷却和冬眠也会在大脑中诱导一些冷休克蛋白，包括RNA结合蛋白RBM3。这些蛋白质与结构可塑性的关系尚不清楚。在这里，我们表明，在神经退行性疾病的小鼠模型中，突触再生受损，与诱导RBM3失败有关。在朊病毒感染和5×FAD（阿尔茨海默型）小鼠中，冷却后突触再生能力下降，与RBM3诱导的丧失平行。海马中RBM3表达的增强防止了这种缺陷，并恢复了冷却后突触重组的能力。此外，通过在RBM3反应丧失之前通过低温提高内源性水平或通过慢病毒递送来实现RBM3过表达，导致5×FAD小鼠和整个朊病毒疾病过程中的持续突触保护，防止行为缺陷和神经元损失并显著延长存活。相比之下，RBM3的敲除加剧了两种模型中的突触丢失，加速了疾病，并阻止了冷却的神经保护作用。因此，至少部分由RBM3应激反应的失败介导的突触再生缺陷导致神经退行性疾病过程中的突触丧失。这些数据支持增强冷休克通路作为神经退行性疾病的潜在保护性疗法。
In the healthy adult brain synapses are continuously remodelled through a process of elimination and formation known as structural plasticity. Reduction in synapse number is a consistent early feature of neurodegenerative diseases, suggesting deficient compensatory mechanisms. While much is known about toxic processes leading to synaptic dysfunction and loss in these disorders, 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 plasticity. We have found that similar changes occur in artificially cooled laboratory rodents. Cooling and hibernation also induce a number cold-shock proteins in the brain, including the RNA binding protein, RBM3. 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 5×FAD (Alzheimer-type) mice, 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. Further, RBM3 over-expression, achieved either by boosting endogenous levels through hypothermia prior to the loss of the RBM3 response, or by lentiviral delivery, resulted in sustained synaptic protection in 5×FAD 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.
登录
查看更多内容
影响因子：
3.3
作者：
Popov, V. I.;Medvedev, N. I.;Stewart, M. G.
通讯作者：
Stewart, M. G.
影响因子：
64.8
作者：
Moreno, Julie A.;Radford, Helois;Peretti, Diego;Steinert, Joern R.;Verity, Nicholas;Martin, Maria Guerra;Halliday, Mark;Morgan, Jason;Dinsdale, David;Ortori, Catherine A.;Barrett, David A.;Tsaytler, Pavel;Bertolotti, Anne;Willis, Anne E.;Bushell, Martin;Mallucci, Giovanna R.
通讯作者：
Mallucci, Giovanna R.
影响因子：
2.3
作者：
Ruediger, J.;Van der Zee, E. A.;Hut, R. A.
通讯作者：
Hut, R. A.
影响因子：
16.2
作者：
Mallucci, Giovanna R.;White, Melanie D.;Collinge, John
通讯作者：
Collinge, John
影响因子：
4.8
作者：
Daniels, Isadora Susan;Zhang, Jianfa;Lee, Cheng Chi
通讯作者：
Lee, Cheng Chi