Development of a lipid-based ferroptosis biomarker for the study of neurodegenerative disease

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Ferroptosis is a recently described cell death modality entirely different from other forms of cell death based on genetic, biochemical and metabolic traits. Research into the mechanisms of ferroptosis - using mostly cellular, genetic and pharmacological approaches in tumor cells and mice - has revealed that it represents an attractive target to treat therapy-refractory and disseminating tumors, as well as degenerative diseases including neurodegeneration. Although lipid peroxidation, the hallmark of ferroptosis, and the key players of ferroptosis, such as glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein-1, are evolutionary highly conserved between mice and man, biomarkers that are specific to the ferroptotic cell death process are lacking. These are, however, of utmost importance not only to unambiguously demonstrate the contribution of ferroptosis to certain disease contexts in patients, but also to be used as a pharmacodynamic marker for the development of novel ferroptosis-based therapies. Therefore, the main goal of this project is to develop and validate a lipid-based biomarker that either alone or in conjunction with a cell death marker can be harnessed to monitor the extent of ferroptosis in extracellular body fluids such as plasma and cerebrospinal fluid. Specifically, we will apply a comprehensive (oxi)lipidomics approach to assess mice specifically lacking GPX4 in certain neuronal subpopulations of the brain and validate these findings in tissue samples of patients suffering from neurodegenerative disease. Moreover, we will interrogate in compound mutant mice whether targeting the phospholipid remodeling process is a valid approach to mitigate certain neurodegenerative diseases. In summary, we aim to provide an utterly awaited and readily accessible (pharmacodynamic) biomarker for monitoring disease progression and for evaluating the phospholipid remodeling axis as an exploitable target for the development of novel therapies to ameliorate neurodegeneration in patients.