Project Details
Projekt
Regulators of inflammation-induced ferroptosis in neurons
Applicants
Professor Dr. Manuel A. Friese; Dr. Marcel Seungsu Woo
Subject Area
Cell Biology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 549844171
Chronic inflammation in the central nervous system (CNS) significantly contributes to neurodegenerative diseases, such as multiple sclerosis (MS), by perpetuating a cycle of neuronal damage and immune activation. This proposal aims to explore the mechanisms that drive inflammation-induced neurodegeneration, focusing on the role of lipid peroxidation and ferroptosis in neurons. Previous research has identified the neuronal inflammatory stress response (NISR) as a critical factor determining neuronal survival or demise. Our preliminary work has shown that inflammatory cues induce excitotoxic cell death in neurons, highlighting the importance of understanding and modulating the NISR for neuroprotection. Given their post-mitotic nature and high metabolic demands, neurons are particularly vulnerable to oxidative stress and lipid peroxidation, potentially leading to ferroptosis. Although several key mediators of ferroptosis have been identified in proliferative cells, our understanding of these processes in neurons remains limited. Our research has shown that chronic CNS inflammation enhances neuronal sensitivity to ferroptosis by disrupting lipid redox homeostasis and altering the balance of GPX4 and SLC7A11 expression and activity. Given the unclear role of SLC7A11 in neurons, we aim to use a combination of genetic and pharmacological approaches to profile the SLC7A11-dependent lipid composition and oxidation in neurons and explore its protective role against ferroptosis during neuroinflammation. Furthermore, we will resolve its expression and subcellular localization using a novel and validated antibody. This targeted analysis of SLC7A11 will be complemented by a comprehensive profiling of neuron-specific responses to ferroptosis using CRISPR and compound screens, aimed at identifying potential treatments to prevent neuronal loss. By elucidating the unique set of neuron-specific ferroptosis modulators, this research could unravel basic principles of ferroptosis in non-proliferative cells, and unlock new therapeutic pathways for MS and other neurodegenerative diseases, addressing an urgent need for effective neuroprotective strategies.
DFG Programme
Priority Programmes
