Lanzillotta Chiara, Zuliani Ilaria, Tramutola Antonella, Barone Eugenio, Blarzino Carla, Folgiero Valentina, Caforio Matteo, Valentini Diletta, Villani Alberto, Locatelli Franco, Butterfield D Allan, Head Elizabeth, Perluigi Marzia, Abisambra Jose F, Di Domenico Fabio
Department of Biochemical Sciences "A. Rossi Fanelli", Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
Department of Pediatric Hematology/Oncology and of Cell and Gene Therapy, Bambino Gesù Children's Hospital, Rome, Italy.
Prog Neurobiol. 2021 Jan;196:101892. doi: 10.1016/j.pneurobio.2020.101892. Epub 2020 Aug 11.
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.
神经生物学中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中，异常的蛋白质构象体会聚集成病理性包涵体，呈现出未折叠蛋白反应的PERK分支的慢性激活。PERK途径的适应性作用包括通过短暂抑制eIF2α来减少翻译，以及通过诱导Nrf2转录因子来产生抗氧化蛋白。相比之下，PERK的长期激活会导致蛋白质合成持续减少并诱导细胞死亡途径。为了进一步研究PERK途径在神经退行性疾病中的作用，我们聚焦于唐氏综合征（DS），在该疾病中，衰老会带来患阿尔茨海默病（AD）的高风险。通过研究人类DS额叶皮质，我们发现了与eIF2α和ATF4下游信号诱导相关的早期且持续的PERK激活。我们还观察到Nrf2反应与PERK解偶联，并且其抗氧化作用在涉及转录抑制因子Bach1的机制中受到抑制。在DS小鼠中对PERK进行药理抑制可减少与eIF2α相关的翻译抑制，并促进Nrf2核转位，有利于挽救Nrf2/Bach1失衡。对在世的DS个体外周细胞的进一步分析为PERK与21三体之间的病理联系提供了有力支持。我们的结果表明，无法调节PERK途径是DS病理的一个特殊特征，它可能是促进细胞功能障碍的关键步骤，而细胞功能障碍在大脑中会积极促成AD的早期发展。
