Combined Transcriptomic and Proteomic Analysis of Perk Toxicity Pathways.

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Endoplasmic reticulum (ER) stress activates protein kinase R-like endoplasmic reticulum kinase (dPerk) in Drosophila.
• dPerk activation is linked to Parkinson's disease models and the unfolded protein response (UPR), contributing to neurodegeneration.
• The Perk pathway is implicated in neuronal death due to chronic reduction of vital proteins.

Purpose of the Study:

• To investigate the transcriptional and translational responses to dPerk activation in Drosophila.
• To identify novel dPerk-regulated genes and understand its impact on protein synthesis.
• To explore potential therapeutic targets for neurodegenerative disorders involving Perk toxicity.

Main Methods:

• Microarray analysis and quantitative proteomics in adult Drosophila overexpressing dPerk.
• Bioinformatics analysis to identify transcriptional and translational changes.
• Investigated the regulation of specific transcripts by Drosophila activating transcription factor 4 (dAtf4).

Main Results:

• Identified "tribbles" and "Heat shock protein 22" as novel dAtf4-regulated transcripts.
• dPerk activation causes translational repression of mitochondrial proteins involved in key metabolic pathways.
• Specific pathways affected include glutathione and nucleotide metabolism, calcium signaling, and iron-sulfur cluster biosynthesis.

Conclusions:

• dPerk activation has significant effects on both gene transcription and protein translation.
• Translational repression of mitochondrial proteins by dPerk impacts cellular functions crucial for neuronal health.
• Enhancing translation of repressed dPerk targets may offer a protective strategy against Perk-induced neurotoxicity.