4.7 Article

The UPR Maintains Proteostasis and the Viability and Function of Hippocampal Neurons in Adult Mice

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MDPI
DOI: 10.3390/ijms241411542

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UPR; neuron; proteostasis; autophagy; lysosome; tau

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The unfolded protein response (UPR) is a major mechanism for maintaining cellular proteostasis. It is involved in regulating neuron viability and function in neurodegenerative diseases, but its role is controversial. While evidence suggests UPR activation in neurons under normal conditions, deficiency of individual UPR branches has no major effect on brain neurons in animals. To determine the physiological role of UPR, mice with double deletion of PERK and ATF6α in neurons were generated. The results showed that UPR is required for maintaining neuronal proteostasis and the viability and function of neurons in the hippocampus of adult mice.
The unfolded protein response (UPR), which comprises three branches: PERK, ATF6 & alpha;, 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 ATF6 & alpha; in neurons. We found that inactivation of PERK and ATF6 & alpha; 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 A & beta;42 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 A & beta; homeostasis) and the viability and function of neurons in the hippocampus of adult mice.

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