Chronic PERK induction promotes Alzheimer-like neuropathology in Down syndrome: Insights for therapeutic intervention: Progress in Neurobiology

C. Lanzillotta, I. Zuliani, A. Tramutola, E. Barone, C. Blarzino, V. Folgiero, M. Caforio, D. Valentini, A. Villani, F. Locatelli, D.A. Butterfield, E. Head, M. Perluigi, J.F. Abisambra, F. Di Domenico

Research output: Contribution to journalArticlepeer-review

Abstract

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. © 2020 Elsevier Ltd
Original languageEnglish
JournalProg. Neurobiol.
Volume196
DOIs
Publication statusPublished - 2021

Keywords

  • Down syndrome
  • Nrf2
  • PERK
  • Protein translation
  • Unfolded protein response
  • activating transcription factor 4
  • antioxidant
  • enzyme inhibitor
  • gsk 2606414
  • gsk 414
  • initiation factor 2alpha
  • protein kinase R
  • protein perk
  • puromycin
  • sc 108071
  • transcription factor Nrf2
  • unclassified drug
  • adult
  • aging
  • Alzheimer disease
  • animal experiment
  • animal model
  • antioxidant activity
  • Article
  • cohort analysis
  • controlled study
  • enzyme inhibition
  • enzyme repression
  • female
  • frontal cortex
  • histopathology
  • human
  • human tissue
  • in vitro study
  • in vivo study
  • male
  • mouse
  • neuropathology
  • neuroprotection
  • nonhuman
  • oxidative stress
  • priority journal
  • protein expression
  • protein function
  • protein induction
  • repressor gene
  • risk factor
  • signal transduction
  • treatment failure
  • unfolded protein response

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