Authors: Chiara Lanzillotta, Ilaria Zuliani, Antonella Tramutola, Jose F. Abisambra, Eugenio Barone, Marzia Perluigi, Fabio Di Domenico
Published: 2020-12-07
DOI: 10.1002/alz.041867
Source: Full article
AbstractBackgroundMany neurodegenerative disorders in which aberrant protein conformers aggregate into pathological inclusions, such as tauopathies, also present endoplasmic reticulum stress and chronic activation of the PERK branch of the unfolded protein response (UPR). The adaptive effects of the PERK pathway include reduction of translation by transient inhibition of eIF2α and antioxidant response via induction of the transcription factor Nrf2. In contrast, prolonged activation of the UPR 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), a secondary tauopathy, in which aging confers a high risk of Alzheimer‐like dementia (AD), Aβ plaques formation and tau tangle deposition. We recently determined that the UPR is dysregulated in a murine DS model. Therefore, our project aims to investigate if restoring PERK pathway, by using a well‐established PERK inhibitor (GSK2606414), could mitigate the early UPR activation and result in reduced brain pathology.MethodTs2Cje (mouse model of DS) at 6 months of age were treated with GSK2606414 a well‐known PERK inhibitor. To target directly the brain, we use the intranasal route. The analysis of the proteins of interest has been carried out by confocal microscopy, Western Blot and real time PCR. Furthermore, we use SUnSET, a non‐radioactive puromycin based approach adapted in vivo, to measure protein synthesis.ResultOur data report that the pharmacological inhibition of PERK, by GSK2606414, ameliorate chronic PERK induction observed in DS mice restoring its downstream signalling aberrantly regulated during pathology. In particular, we demonstrate, in Ts2Cje treated mice the rescue from eIF2a‐mediated disruption of protein synthesis. In addition, we show that the compound was able to promote the Nrf2‐related antioxidant response reducing protein oxidative damage. Such effect was obtained by the increase of PI3K interaction with Nrf2 and by the restrain of Bach1 binding to ARE sequences.ConclusionOur study provides further insights about the role of PERK in DS pathology and in the development of AD, proposing PERK inhibitors as novel therapeutic agents able to rescue trisomic‐related defects of proteostasis and antioxidant response.