A major challenge in neurobiology is the identification of the mechanisms by which protein misfolding leads to cellular toxicity. Many neurodegenerative disorders, in which aberrant protein conformers aggregate into pathological inclusions, present the chronic activation of the PERK branch of the unfolded protein response. The adaptive effects of the PERK pathway include reduction of translation by transient inhibition of eIF2α and antioxidant protein production via induction of Nrf2 transcription factor. In contrast, PERK prolonged activation leads to sustained reduction in protein synthesis and induction of cell death pathways. To further investigate the role of the PERK pathway in neurodegenerative disorders, we focused on Down syndrome (DS), in which aging confers a high risk of Alzheimer disease (AD). By investigating human DS frontal cortices, we found early and sustained PERK activation associated with the induction of eIF2α and ATF4 downstream signals. We also observed that the Nrf2 response is uncoupled from PERK and its antioxidant effects are repressed in a mechanism implicating the transcription repressor Bach1. The pharmacological inhibition of PERK in DS mice reduced eIF2α-related translational repression and promoted Nrf2 nuclear translocation, favoring the rescue of Nrf2/Bach1 imbalance. The further analysis of peripheral cells from living DS individuals provided strong support of the pathological link between PERK and trisomy 21. Our results suggest that failure to regulate the PERK pathway is a peculiar characteristic of DS pathology and it may represent an essential step to promote cellular dysfunction, which actively contributes in the brain to the early development of AD.

神经生物学的一个主要挑战是确定蛋白质错误折叠导致细胞毒性的机制。许多神经退行性疾病，其中异常蛋白质构象异构体聚集成病理包涵体，呈现未折叠蛋白质反应的 PERK 分支的慢性激活。PERK 通路的适应性效应包括通过瞬时抑制 eIF2α 和通过诱导 Nrf2 转录因子产生抗氧化蛋白来减少翻译。相比之下，PERK 长期激活导致蛋白质合成持续减少和细胞死亡途径的诱导。为了进一步研究 PERK 通路在神经退行性疾病中的作用，我们专注于唐氏综合症 (DS)，其中衰老会导致阿尔茨海默病 (AD) 的高风险。通过研究人类 DS 额叶皮质，我们发现早期和持续的 PERK 激活与 eIF2α 和 ATF4 下游信号的诱导相关。我们还观察到 Nrf2 反应与 PERK 脱钩，其抗氧化作用在涉及转录抑制因子 Bach1 的机制中受到抑制。DS 小鼠中 PERK 的药理学抑制减少了 eIF2α 相关的翻译抑制并促进了 Nrf2 核易位，有利于挽救 Nrf2/Bach1 失衡。对活体 DS 个体外周细胞的进一步分析为 PERK 和 21 三体之间的病理联系提供了强有力的支持。功能障碍，