Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/135093
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Type: | Journal article |
Title: | Selective ferroptosis vulnerability due to familial Alzheimer's disease presenilin mutations. |
Author: | Greenough, M.A. Lane, D.J.R. Balez, R. Anastacio, H.T.D. Zeng, Z. Ganio, K. McDevitt, C.A. Acevedo, K. Belaidi, A.A. Koistinaho, J. Ooi, L. Ayton, S. Bush, A.I. |
Citation: | Cell Death and Differentiation, 2022; 29(11):1404-1-1404-14 |
Publisher: | Springer Nature |
Issue Date: | 2022 |
ISSN: | 1350-9047 1476-5403 |
Statement of Responsibility: | Mark A. Greenough, Darius J. R. Lane, Rachelle Balez, Helena Targa Dias Anastacio, Zhiwen Zeng, Katherine Ganio, Christopher A. McDevitt, Karla Acevedo, Abdel Ali Belaidi, Jari Koistinaho, Lezanne Ooi, Scott Ayton, and Ashley I. Bush |
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 expression, which then controls GPX4 expression by regulating the supply of selenium into the cell since LRP8 is the uptake receptor for selenoprotein P. Selenium uptake is thus disrupted by presenilin FAD mutations, suppressing GPX4 expression. Therefore, presenilin mutations may promote neurodegeneration by derepressing ferroptosis, which has implications for disease-modifying therapeutics. |
Keywords: | Humans Alzheimer Disease Selenium Mutation Amyloid Precursor Protein Secretases Presenilin-1 Presenilins Ferroptosis |
Rights: | © The Author(s) 2022 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/. |
DOI: | 10.1038/s41418-022-01003-1 |
Published version: | http://dx.doi.org/10.1038/s41418-022-01003-1 |
Appears in Collections: | Molecular and Biomedical Science publications |
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