Integration of omics to explore novel disease pathways in Down Syndrome neurodegeneration – Focusing on integrated stress response

Abstract

Down Syndrome is characterized by the trisomy of chromosome 21, leading to widespread molecular and neurological alterations, including early-onset Alzheimer's disease. Emerging evidence highlights the role of RNA metabolism, RNA-binding proteins, and stress granules in these processes. The integrated stress response, a key regulator of translation and protein homeostasis, may be particularly disrupted in DS due to the overexpression of genes involved in the balance between protein degradation and RNA transcription. However, its impact on neurodegeneration in DS remains poorly understood. This project aims to integrate transcriptomic and proteomic data from human and animal models with Down Syndrome to dissect the interplay between integrated stress response, RNA-binding proteins, and stress granule dynamics. By identifying key molecular disruptions in RNA homeostasis and protein synthesis, we aim to investigate novel disease-driving mechanisms that can be conserved among species. These insights will likely help to establish ISR as a potential therapeutic target, advancing our understanding of DS-related neurodegenerative pathways that could be behind the age-related neurodegeneration observed in DS.