Ferroptosis in Schizophrenia

Summary Schizophrenia is a debilitating mental illness that disrupts the functioning of the mind, with onset typically occurring in young adulthood. Impairments in certain cognitive functions, such as working memory, are core features of Sz, which are not addressed for existing drug targets. Our general hypothesis is that schizophrenia is a complex disease resulting from a loss-of-function of key pathways that govern neurodevelopment, neurotransmission, intracellular redox state and synaptic connectivity. Our data indicate that iron is elevated in the orbitofrontal cortex in post mortem brain samples from individuals with schizophrenia relative to age- and sex-matched controls. We propose that a rise of cytosolic iron is upstream of key lesions associated with negative and cognitive symptoms of schizophrenia, including neuronal development (e.g., parvalbumin-interneurons and synaptic pruning), neurotransmission (e.g., GABAergic and glutamatergic pathways), as well as iron homeostasis, antioxidant defence (e.g., haem oxygenases), and ferroptosis (e.g., an iron-dependent pathway for lipid peroxidation recently associated with loss of parvalbumin-interneurons). The project aims to investigate the status of proteins involved in iron metabolim as well as levels of markers of oxidative stress.

Project Details

Our working hypothesis is that an elevation of iron in the brain of individuals with schizophrenia drives key neurochemical aspects of lipid peroxidative stress and hyperdopaminergia in the orbital frontal cortex that are known to be relevant to schizophrenia pathophysiology. Post mortem brain samples will be homogenized and centrifuged to collect protein supernantants. Oxidative stress induced cellular toxicity caused by unregulated lipid or iron metabolism will be biochemically measured DNA/RNA damage (8-hydroxydeoxyguanosine; 8-OHdG assay), lipid peroxidation (thiobarbituric acid reactive substances; TBARS assay) and protein carbonylation (Oxyblot assay). Proteins related to iron metabolims will be detected by Western blot.