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Selective ferroptosis vulnerability due to familial Alzheimer���s disease presenilin mutations

Journal Article


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 ��-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.

UOW Authors


Publication Date


  • 2022

Citation


  • Greenough, M. A., Lane, D. J. R., Balez, R., Anastacio, H. T. D., Zeng, Z., Ganio, K., . . . Bush, A. I. (2022). Selective ferroptosis vulnerability due to familial Alzheimer���s disease presenilin mutations. Cell Death and Differentiation, 29(11), 2123-2136. doi:10.1038/s41418-022-01003-1

Scopus Eid


  • 2-s2.0-85128654802

Start Page


  • 2123

End Page


  • 2136

Volume


  • 29

Issue


  • 11

Place Of Publication


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 ��-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.

UOW Authors


Publication Date


  • 2022

Citation


  • Greenough, M. A., Lane, D. J. R., Balez, R., Anastacio, H. T. D., Zeng, Z., Ganio, K., . . . Bush, A. I. (2022). Selective ferroptosis vulnerability due to familial Alzheimer���s disease presenilin mutations. Cell Death and Differentiation, 29(11), 2123-2136. doi:10.1038/s41418-022-01003-1

Scopus Eid


  • 2-s2.0-85128654802

Start Page


  • 2123

End Page


  • 2136

Volume


  • 29

Issue


  • 11

Place Of Publication