Professor Ashley Bush, Melbourne Dementia Research Centre, The Florey Institute : "Ferroptosis, iron and neurodegenerative disease"
Speaker:
Professor Ashley Bush
Director of the Melbourne Dementia Research Centre
The Florey Institute, Parkville VIC
Title: "Ferroptosis, iron and neurodegenerative disease"
Abstract:
Recent research has implicated increased brain iron as a trait that can propel various neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Motor Neuron disease (MND) and the complications of stroke. During childhood and reproductive life, iron recruitment is geared towards avoiding iron deficiency, but there is no natural mechanism for off-loading excess iron. After reproductive life the systems that harvest iron so efficiently do not turn off, and lead to accumulation in tissues that are not normally shed, like brain. In Alzheimer's disease brain iron elevation is associated with the rate of cognitive loss, lipid peroxidation products and features of the regulated cell death mechanism, ferroptosis. APP functions to promote iron efflux in neurons by stabilizing surface ferroportin. We have recently found that amyloidogenic processing of APP induced pharmacologically or genetically (familial mutations) causes iron retention. This raises a non-amyloid pathogenic mechanism for familial AD. Anti-ferroptosis agents have been effective in animal models of neurodegenerative disease, and a recent phase 2 clinical trial of the anti-ferroptotic chelator deferiprone in Parkinson’s disease lowered nigral iron and improved clinical readouts. We are currently testing this drug in a phase 2 RCT in Alzheimer’s disease. CuATSM, has recently reported benefits in phase 1 studies of PD and MND, and we have identified that it possesses potent anti-ferroptotic properties.
References:
Stockwell et al. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell, 171, 273–285 (2017).
Ayton et al. Brain iron is associated with accelerated cognitive decline in people with Alzheimer pathology. Molecular Psychiatry, 45: 358-67 (2019).
Southon et al. CuII(atsm) inhibits ferroptosis: implications for treatment of neurodegenerative disease. British Journal of Pharmacology, 177, 656-667 (2019).
Tsatsanis et al. Amyloidogenic Processing of Alzheimer's Disease Beta-Amyloid Precursor Protein Induces Cellular Iron Retention. Molecular Psychiatry, (2020) 10.1038/s41380-020-0762-0
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