10.3390/ijms22094598 Combined Transcriptomic and Proteomic Analysis of Perk Toxicity Pathways http://orcid.org/0000-0002-6839-9391 Popovic Rebeka Dr. MRC Toxicology Unit, University of Cambridge, Gleeson Building, Tennis Court Road, Cambridge CB2 1QR, UK rp636@cam.ac.uk Celardo Ivana Dr. MRC Toxicology Unit, University of Cambridge, Gleeson Building, Tennis Court Road, Cambridge CB2 1QR, UK ivana.celardo@uniroma1.it Yu Yizhou Dr. MRC Toxicology Unit, University of Cambridge, Gleeson Building, Tennis Court Road, Cambridge CB2 1QR, UK yzy21@cam.ac.uk Costa Ana C. Dr. MRC Toxicology Unit, University of Cambridge, Gleeson Building, Tennis Court Road, Cambridge CB2 1QR, UK anacarinaecosta@gmail.com Loh Samantha H. Y. Dr. MRC Toxicology Unit, University of Cambridge, Gleeson Building, Tennis Court Road, Cambridge CB2 1QR, UK shyl2@cam.ac.uk http://orcid.org/0000-0002-3019-4809 Martins L. Miguel Dr. MRC Toxicology Unit, University of Cambridge, Gleeson Building, Tennis Court Road, Cambridge CB2 1QR, UK martins.lmiguel@gmail.com 27 04 2021 22 9 23 04 2021 e4598 In Drosophila, endoplasmic reticulum (ER) stress activates the protein kinase R-like endoplasmic reticulum kinase (dPerk). dPerk can also be activated by defective mitochondria in fly models of Parkinson’s disease caused by mutations in pink1 or parkin. The Perk branch of the unfolded protein response (UPR) has emerged as a major toxic process in neurodegenerative disorders causing a chronic reduction in vital proteins and neuronal death. In this study, we combined microarray analysis and quantitative proteomics analysis in adult flies overexpressing dPerk to investigate the relationship between the transcriptional and translational response to dPerk activation. We identified tribbles and Heat shock protein 22 as two novel Drosophila activating transcription factor 4 (dAtf4) regulated transcripts. Using a combined bioinformatics tool kit, we demonstrated that the activation of dPerk leads to translational repression of mitochondrial proteins associated with glutathione and nucleotide metabolism, calcium signalling and iron-sulphur cluster biosynthesis. Further efforts to enhance these translationally repressed dPerk targets might offer protection against Perk toxicity. UK Research and Innovation MC_UU_00025/3 (RG94521) © 1996-2021 MDPI (Basel, Switzerland) 2021 This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited Drosophila Drosophila protein kinase RNA (PKR)-like ER kinase (dPerk) ER stress unfolded protein response activating transcription factor 4 (ATF4) International Journal of Molecular Sciences Int J Mol Sci 1422-0067 MDPI