简体中文
萃智医药
TRIZ PHARMA
Trizpharm@aliyun.com
+86-0371-86597269 / 53392065

产品中心

PRODUCTS

▶ 当前位置:
冷休克蛋白的神经保护作用

突触联系在冬眠的动物中会失去,但当温度上升时又会重新形成。RBM3是大脑中响应于温度降低而产生的一种能够结合RNA的冷休克蛋白,但它在突触可塑性中的功能却不知道。

Giovanna Mallucci及同事发现,小鼠神经退化病模型中受损的突触再生与RMB3未能得到诱导相关。RMB3的过度表达能恢复突触联系的形成,同时其功能的丧失又会触发进一步的再生缺陷。

这些发现表明,冷休克蛋白是内源修复过程的构成部分,也是神经退化病中神经保护的可能治疗目标。


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