Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy.
Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy.
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DOI：
10.1093/brain/aws143
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发表时间：
2012-07
期刊：
影响因子：
--
通讯作者：
Goedert M
中科院分区：
文献类型：
--
作者：
Schaeffer V;Lavenir I;Ozcelik S;Tolnay M;Winkler DT;Goedert M
不可溶蛋白质的积累是几种神经退行性疾病的病理特征。Tau病是由tau蛋白的功能障碍和聚集引起的，细胞蛋白降解途径的损伤可能是其发病机制之一。因此，自噬的缺陷会导致神经退化，而自噬的激活则对某些蛋白病变具有保护作用。关于自噬在人类紧张症动物模型中的作用，人们知之甚少。在本报告中，我们用生化和免疫组织化学分析的方法，评估了海藻糖对自噬的刺激作用在转基因小鼠的自噬效应中的作用。用体视学方法评价神经元存活情况。自噬在大脑中被激活，含有tau包涵体的神经元数量显著减少，不溶性tau蛋白的数量也显著减少。Tau聚集体的减少与大脑皮层和脑干中神经元存活率的改善有关。我们还观察到p62蛋白的减少，这表明它可能有助于tau包涵体的去除。海藻糖未能激活脊髓中的自噬，对肌糖不溶性tau的水平没有影响。因此，海藻糖对人突变型P301S tau转基因小鼠的运动损伤没有影响。我们的发现提供了支持tau聚集体通过自噬降解的直接证据。自噬的激活可能值得在人类自噬疗法的背景下进行研究。
The accumulation of insoluble proteins is a pathological hallmark of several neurodegenerative disorders. Tauopathies are caused by the dysfunction and aggregation of tau protein and an impairment of cellular protein degradation pathways may contribute to their pathogenesis. Thus, a deficiency in autophagy can cause neurodegeneration, while activation of autophagy is protective against some proteinopathies. Little is known about the role of autophagy in animal models of human tauopathy. In the present report, we assessed the effects of autophagy stimulation by trehalose in a transgenic mouse model of tauopathy, the human mutant P301S tau mouse, using biochemical and immunohistochemical analyses. Neuronal survival was evaluated by stereology. Autophagy was activated in the brain, where the number of neurons containing tau inclusions was significantly reduced, as was the amount of insoluble tau protein. This reduction in tau aggregates was associated with improved neuronal survival in the cerebral cortex and the brainstem. We also observed a decrease of p62 protein, suggesting that it may contribute to the removal of tau inclusions. Trehalose failed to activate autophagy in the spinal cord, where it had no impact on the level of sarkosyl-insoluble tau. Accordingly, trehalose had no effect on the motor impairment of human mutant P301S tau transgenic mice. Our findings provide direct evidence in favour of the degradation of tau aggregates by autophagy. Activation of autophagy may be worth investigating in the context of therapies for human tauopathies.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
3.1
作者：
Goedert, Michel;Spillantini, Maria Grazia
通讯作者：
Spillantini, Maria Grazia
影响因子：
2.5
作者：
GOEDERT, M;JAKES, R;VANMECHELEN, E
通讯作者：
VANMECHELEN, E
影响因子：
4.2
作者：
Liu, Ying-Hua;Wei, Wei;Wang, Jian-Zhi
通讯作者：
Wang, Jian-Zhi
影响因子：
5.3
作者：
Bedford, Lynn;Hay, David;Mayer, R. John
通讯作者：
Mayer, R. John