Abstract
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.
Highlights
As we age, neurodegenerative diseases are becoming a prominent health problem worldwide
We chose to heat-shock the flies for 15 h, as this timepoint provided the highest level of detected dPerk expression by assessment of its mRNA levels (Figure 1b) and corresponded to a peak of expression of Nmdmc, a Drosophila activating transcription factor 4 (dAtf4) target (Figure 1c) [20]
While this modification leads to global inhibition of protein synthesis, it simultaneously enhances the translation of selected mRNAs, such as that of the transcription factor activating transcription factor 4 (ATF4) [58], eliciting a gene expression programme designed to confer cellular resistance to stress
Summary
Neurodegenerative diseases are becoming a prominent health problem worldwide. Despite large-scale efforts to treat these diseases, current therapies only offer symptomatic relief without the possibility of curative treatments. The unique genetic, pathological and clinical signatures of individual neurodegenerative diseases have focused scientific research on the disease-specific protein-centric mechanism of pathology. It is becoming increasingly clear that neurodegenerative diseases share a common subcellular signature. The unfolded protein response (UPR) is perceived to be a generic feature of most neurodegenerative diseases (reviewed in [1]). Modulation of the UPR represents a promising target for therapies designed to delay or prevent neurodegeneration (reviewed in [2])
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