Death Induced by Survival gene Elimination (DISE) correlates with neurotoxicity in Alzheimer’s disease and aging

Bidur Paudel, Si-Yeon Jeong, Carolina Pena Martinez, Alexis Rickman, Ashley Haluck-Kangas, Elizabeth T. Bartom, Kristina Fredriksen, Amira Affaneh, John A. Kessler, Joseph R. Mazzulli, Andrea E. Murmann, Emily Rogalski, Changiz Geula, Adriana Ferreira, Bradlee L. Heckmann, Douglas R. Green, Katherine R. Sadleir, Robert Vassar and Marcus E. Peter ()
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Bidur Paudel: Northwestern University
Si-Yeon Jeong: Northwestern University
Carolina Pena Martinez: USF Health Byrd Alzheimer’s Center and Neuroscience Institute; Department of Molecular Medicine, Morsani College of Medicine
Alexis Rickman: USF Health Byrd Alzheimer’s Center and Neuroscience Institute; Department of Molecular Medicine, Morsani College of Medicine
Ashley Haluck-Kangas: Northwestern University
Elizabeth T. Bartom: Northwestern University
Kristina Fredriksen: Northwestern University
Amira Affaneh: Northwestern University
John A. Kessler: Northwestern University
Joseph R. Mazzulli: Northwestern University
Andrea E. Murmann: Northwestern University
Emily Rogalski: Northwestern University
Changiz Geula: Northwestern University
Adriana Ferreira: Northwestern University
Bradlee L. Heckmann: USF Health Byrd Alzheimer’s Center and Neuroscience Institute; Department of Molecular Medicine, Morsani College of Medicine
Douglas R. Green: St. Jude Children’s Research Hospital
Katherine R. Sadleir: Northwestern University
Robert Vassar: Northwestern University
Marcus E. Peter: Northwestern University

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Alzheimer’s disease (AD) is characterized by progressive neurodegeneration, but the specific events that cause cell death remain poorly understood. Death Induced by Survival gene Elimination (DISE) is a cell death mechanism mediated by short (s) RNAs acting through the RNA-induced silencing complex (RISC). DISE is thus a form of RNA interference, in which G-rich 6mer seed sequences in the sRNAs (position 2-7) target hundreds of C-rich 6mer seed matches in genes essential for cell survival, resulting in the activation of cell death pathways. Here, using Argonaute precipitation and RNAseq (Ago-RP-Seq), we analyze RISC-bound sRNAs to quantify 6mer seed toxicity in several model systems. In mouse AD models and aging brain, in induced pluripotent stem cell-derived neurons from AD patients, and in cells exposed to Aβ42 oligomers, RISC-bound sRNAs show a shift to more toxic 6mer seeds compared to controls. In contrast, in brains of “SuperAgers”, humans over age 80 who have superior memory performance, RISC-bound sRNAs are shifted to more nontoxic 6mer seeds. Cells depleted of nontoxic sRNAs are sensitized to Aβ42-induced cell death, and reintroducing nontoxic RNAs is protective. Altogether, the correlation between DISE and Aβ42 toxicity suggests that increasing the levels of nontoxic miRNAs in the brain or blocking the activity of toxic RISC-bound sRNAs could ameliorate neurodegeneration.

Date: 2024
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DOI: 10.1038/s41467-023-44465-8

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