Journal article
Selective ferroptosis vulnerability due to familial Alzheimer’s disease presenilin mutations
MA Greenough, DJR Lane, R Balez, HTD Anastacio, Z Zeng, K Ganio, CA McDevitt, K Acevedo, AA Belaidi, J Koistinaho, L Ooi, S Ayton, AI Bush
Cell Death and Differentiation | Published : 2022
Abstract
Mutations in presenilin 1 and 2 (PS1 and PS2) cause autosomal dominant familial Alzheimer’s disease (FAD). Ferroptosis has been implicated as a mechanism of neurodegeneration in AD since neocortical iron burden predicts Alzheimer’s disease (AD) progression. We found that loss of the presenilins dramatically sensitizes multiple cell types to ferroptosis, but not apoptosis. FAD causal mutations of presenilins similarly sensitizes cells to ferroptosis. The presenilins promote the expression of GPX4, the selenoprotein checkpoint enzyme that blocks ferroptosis by quenching the membrane propagation of lethal hydroperoxyl radicals. Presenilin γ-secretase activity cleaves Notch-1 to signal LRP8 expr..
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Funding Acknowledgements
This work was supported by funds from the National Health & Medical Research Council (NHMRC) of Australia and Australian Research Council (ARC). MAG is a recipient of an ARC-NHMRC Dementia Research Development Fellowships. LO is supported by a NHMRC of Australia Boosting Dementia Research Leadership Fellowship. SA is supported by a NHMRC Leadership Fellowship. We also thank Dementia Australia for their generous support. The Florey Institute also acknowledges financial support from the Victorian Government's Operational Infrastructure Support Program. Open Access funding enabled and organized by CAUL and its Member Institutions.