cPKCγ-mediated down-regulation of UCHL1 alleviates ischaemic neuronal injuries by decreasing autophagy via ERK-mTOR pathway.
cPKCγ-mediated down-regulation of UCHL1 alleviates ischaemic neuronal injuries by decreasing autophagy via ERK-mTOR pathway.
复制标题
DOI：
10.1111/jcmm.13275
复制
发表时间：
2017-12
影响因子：
5.3
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Zhang D;Han S;Wang S;Luo Y;Zhao L;Li J
中风是世界上主要的死亡原因之一，但其潜在的机制仍不清楚。传统的蛋白激酶C（cPKC）γ和泛素C末端水解酶L1（UCHL 1）都是神经元特异性蛋白。在小鼠大脑中动脉闭塞（MCAO）1小时/再灌注24小时和皮层神经元氧糖剥夺（OGD）1小时/再给氧24小时模型中，我们发现cPKCγ基因敲除显著加重了缺血性损伤，同时增加了裂解的（Cl）-caspase-3和LC 3-I蛋白水解产物LC 3-II的水平，以及TUNEL阳性细胞占总神经元的比例。此外，cPKCγ基因敲除还可通过核因子κB抑制剂α（IκB-α）/核因子κB（NF-κB）途径上调UCHL 1的mRNA水平，从而增加UCHL 1蛋白的表达。UCHL 1的抑制剂和shRNA都显著降低了LC 3-II/总LC 3的比例，这有助于缺血性卒中后神经元的存活，但没有改变Cl-caspase-3的水平。此外，UCHL 1 shRNA逆转了cPKCγ对mTOR和ERK磷酸化水平的影响，而不是AMPK和GSK-3β。结论：cPKCγ激活通过抑制UCHL 1表达减轻小鼠和皮层神经元的缺血性损伤，UCHL 1可能通过ERK‐mTOR通路负性调节自噬。
Stroke is one of the leading causes of death in the world, but its underlying mechanisms remain unclear. Both conventional protein kinase C (cPKC)γ and ubiquitin C‐terminal hydrolase L1 (UCHL1) are neuron‐specific proteins. In the models of 1‐hr middle cerebral artery occlusion (MCAO)/24‐hr reperfusion in mice and 1‐hr oxygen–glucose deprivation (OGD)/24‐hr reoxygenation in cortical neurons, we found that cPKCγ gene knockout remarkably aggravated ischaemic injuries and simultaneously increased the levels of cleaved (Cl)‐caspase‐3 and LC3‐I proteolysis product LC3‐II, and the ratio of TUNEL‐positive cells to total neurons. Moreover, cPKCγ gene knockout could increase UCHL1 protein expression via elevating its mRNA level regulated by the nuclear factor κB inhibitor alpha (IκB‐α)/nuclear factor κB (NF‐κB) pathway in cortical neurons. Both inhibitor and shRNA of UCHL1 significantly reduced the ratio of LC3‐II/total LC3, which contributed to neuronal survival after ischaemic stroke, but did not alter the level of Cl‐caspase‐3. In addition, UCHL1 shRNA reversed the effect of cPKCγ on the phosphorylation levels of mTOR and ERK rather than that of AMPK and GSK‐3β. In conclusion, our results suggest that cPKCγ activation alleviates ischaemic injuries of mice and cortical neurons through inhibiting UCHL1 expression, which may negatively regulate autophagy through ERK‐mTOR pathway.
登录
查看更多内容
UCHL1调制对α-链核病模型中α-核蛋白的差异作用。
影响因子：
3.7
作者：
Cartier AE;Ubhi K;Spencer B;Vazquez-Roque RA;Kosberg KA;Fourgeaud L;Kanayson P;Patrick C;Rockenstein E;Patrick GN;Masliah E
通讯作者：
Masliah E
影响因子：
3
作者：
Balkaya, Mustafa;Kroeber, Jan;Endres, Matthias
通讯作者：
Endres, Matthias
影响因子：
5.3
作者：
Carrieri C;Forrest AR;Santoro C;Persichetti F;Carninci P;Zucchelli S;Gustincich S
通讯作者：
Gustincich S
影响因子：
5.3
作者：
Avila, A;Silverman, N;Moscat, J
通讯作者：
Moscat, J
影响因子：
6.3
作者：
Chen, JL;Zhang, CL;Chopp, M
通讯作者：
Chopp, M