Ameliorating cellular stress in neurodegeneration

Neurodegenerative diseases such as Alzheimer’s (AD) and Parkinson’s (PD) are marked by progressive neuronal loss and lack effective disease-modifying therapies. A common thread across these disorders is chronic cellular stress, including oxidative and ER stress, which drives damage through mechanisms like lipid peroxidation and protein misfolding. We aim to decode and restore stress-related homeostasis in AD by leveraging hypothesis-free CRISPR screens in iPSC-derived human neurons. Building on screens targeting oxidative stress, ER stress, and RBM3 cold shock protein, we have uncovered novel, actionable targets. These discoveries are made possible through the development and application of physiologically relevant in vitro models—tools that will be further discussed during this presentation.