Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
Institute for Translational Neuroscience, University of Minnesota, 2101 6th Street SE, WMBB4-140, Minneapolis, MN 55455, USA.
Int J Mol Sci. 2023 Jul 16;24(14):11542. doi: 10.3390/ijms241411542.
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.
未折叠蛋白反应 (UPR) 由三条分支组成：PERK、ATF6α 和 IRE1，是维持细胞蛋白平衡的主要机制。许多研究表明，UPR 是调节各种神经退行性疾病中神经元存活和功能的主要参与者；然而，其在神经退行性变中的作用存在很大争议。此外，尽管有证据表明 UPR 在正常条件下的神经元中被激活，但 UPR 的单个分支的缺失对动物的大脑神经元没有重大影响。目前尚不清楚 UPR 是否以及如何在正常和疾病条件下参与调节神经元蛋白平衡。为了确定 UPR 在神经元中的生理作用，我们生成了神经元中 PERK 和 ATF6α 双缺失的小鼠。我们发现，神经元中 PERK 和 ATF6α 的失活导致溶酶体功能障碍（表现为 v-ATPase 的 V0a1 亚基表达减少和组织蛋白酶 D 活性降低），自噬流受损（表现为 LC3-II/LC3-I 比值增加和 p62 水平升高），以及海马体中 p-tau 和 Aβ42 的积累，并导致成年小鼠空间记忆受损、海马体 LTP 受损和海马体退化。这些结果表明，UPR 是维持神经元蛋白平衡（特别是 tau 和 Aβ 平衡）以及成年小鼠海马体中神经元存活和功能所必需的。
