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


Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
18 Jan 2024
Historique:
received: 02 02 2023
accepted: 13 12 2023
medline: 19 1 2024
pubmed: 19 1 2024
entrez: 18 1 2024
Statut: epublish

Résumé

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.

Identifiants

pubmed: 38238311
doi: 10.1038/s41467-023-44465-8
pii: 10.1038/s41467-023-44465-8
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

264

Informations de copyright

© 2024. The Author(s).

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Auteurs

Bidur Paudel (B)

Department of Medicine/Division Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.

Si-Yeon Jeong (SY)

Department of Medicine/Division Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
Ministry of Food and Drug Safety, Pharmaceutical Safety Bureau, Pharmaceutical Policy Division 187, Osongsaengmyeong 2-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do, Republic of Korea.

Carolina Pena Martinez (CP)

USF Health Byrd Alzheimer's Center and Neuroscience Institute; Department of Molecular Medicine, Morsani College of Medicine, Tampa, FL, 33613, USA.

Alexis Rickman (A)

USF Health Byrd Alzheimer's Center and Neuroscience Institute; Department of Molecular Medicine, Morsani College of Medicine, Tampa, FL, 33613, USA.

Ashley Haluck-Kangas (A)

Department of Medicine/Division Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.

Elizabeth T Bartom (ET)

Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
Department of Preventive Medicine/Division of Biostatistics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.

Kristina Fredriksen (K)

Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.

Amira Affaneh (A)

Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.

John A Kessler (JA)

Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.

Joseph R Mazzulli (JR)

Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.

Andrea E Murmann (AE)

Department of Medicine/Division Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.

Emily Rogalski (E)

Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
Healthy Aging & Alzheimer's Research Care (HAARC) Center, Department of Neurology, The University of Chicago, Chicago, IL, 60637, USA.

Changiz Geula (C)

Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.

Adriana Ferreira (A)

Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.

Bradlee L Heckmann (BL)

USF Health Byrd Alzheimer's Center and Neuroscience Institute; Department of Molecular Medicine, Morsani College of Medicine, Tampa, FL, 33613, USA.

Douglas R Green (DR)

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.

Katherine R Sadleir (KR)

Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.

Robert Vassar (R)

Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.

Marcus E Peter (ME)

Department of Medicine/Division Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. m-peter@northwestern.edu.
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. m-peter@northwestern.edu.

Classifications MeSH