Combined Transcriptomic and Proteomic Analysis of Perk Toxicity Pathways

• Main Authors: Rebeka Popovic, Ivana Celardo, Yizhou Yu, Ana C. Costa, Samantha H. Y. Loh, L. Miguel Martins
• Format: Article
• Language: English
• Published: MDPI AG 2021-04-01
• Series: International Journal of Molecular Sciences
• Subjects: <i>Drosophila</i>; <i>Drosophila</i> protein kinase RNA (PKR)-like ER kinase (dPerk); ER stress; unfolded protein response; activating transcription factor 4 (ATF4)
• Online Access: https://www.mdpi.com/1422-0067/22/9/4598
• ISSN: 1661-6596; 1422-0067

In <i>Drosophila</i>, 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 <i>pink1</i> or <i>parkin</i>. 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 <i>tribbles</i> and <i>Heat shock protein 22 </i>as two novel <i>Drosophila</i> 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.