The UPR Maintains Proteostasis and the Viability and Function of Hippocampal Neurons in Adult Mice.
The UPR Maintains Proteostasis and the Viability and Function of Hippocampal Neurons in Adult Mice.
复制标题
DOI：
10.3390/ijms241411542
复制
发表时间：
2023-07-16
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
未折叠蛋白反应（UPR）包括三个分支：PERK、ATF6α和IRE1，是维持细胞蛋白质稳态的主要机制。许多研究表明，在各种神经退行性疾病中，UPR是调节神经元活力和功能的主要参与者；然而，它在神经退行性变中的作用是非常有争议的。此外，虽然有证据表明在正常情况下神经元中会激活UPR，但缺乏UPR的单个分支对动物的大脑神经元没有重大影响。目前尚不清楚UPR是否或如何参与调节正常和疾病条件下的神经元蛋白酶抑制。为了确定UPR在神经元中的生理作用，我们制造了神经元中PERK和ATF6α双缺失的小鼠。我们发现，神经元PERK和ATF6α的失活导致成年小鼠溶酶体功能障碍（表现为v-ATPase V0a1亚基表达降低，组织蛋白酶D激活降低），自噬通量受损（表现为LC3-II/LC3-I比值升高，p62水平升高），p-tau和a - β42在海马中积累，导致空间记忆受损，海马LTP受损，海马变性。这些结果表明，UPR对于维持成年小鼠海马神经元的蛋白质平衡（特别是tau和β稳态）以及神经元的活力和功能是必需的。
The unfolded protein response (UPR), which comprises three branches: PERK, ATF6α, and IRE1, is a major mechanism for maintaining cellular proteostasis. Many studies show that the UPR is a major player in regulating neuron viability and function in various neurodegenerative diseases; however, its role in neurodegeneration is highly controversial. Moreover, while evidence suggests activation of the UPR in neurons under normal conditions, deficiency of individual branches of the UPR has no major effect on brain neurons in animals. It remains unclear whether or how the UPR participates in regulating neuronal proteostasis under normal and disease conditions. To determine the physiological role of the UPR in neurons, we generated mice with double deletion of PERK and ATF6α in neurons. We found that inactivation of PERK and ATF6α in neurons caused lysosomal dysfunction (as evidenced by decreased expression of the V0a1 subunit of v-ATPase and decreased activation of cathepsin D), impairment of autophagic flux (as evidenced by increased ratio of LC3-II/LC3-I and increased p62 level), and accumulation of p-tau and Aβ42 in the hippocampus, and led to impairment of spatial memory, impairment of hippocampal LTP, and hippocampal degeneration in adult mice. These results suggest that the UPR is required for maintaining neuronal proteostasis (particularly tau and Aβ homeostasis) and the viability and function of neurons in the hippocampus of adult mice.
登录
查看更多内容
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
12.7
作者：
Duran-Aniotz, Claudia;Cornejo, Victor Hugo;Hetz, Claudio
通讯作者：
Hetz, Claudio
DOI：
10.1097/nen.0000000000000224
发表时间：
2015-08-01
影响因子：
3.2
作者：
Bruch, Julius;Kurz, Carolin;Hoeglinger, Guenter U.
通讯作者：
Hoeglinger, Guenter U.
影响因子：
5.6
作者：
Ghemrawi R;Khair M
通讯作者：
Khair M
影响因子：
12.7
作者：
Guo T;Noble W;Hanger DP
通讯作者：
Hanger DP