Biological Sciences Division
Published January 18, 2024 | Version v1
Journal article Open

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

Creators

  • 1. Northwestern University
  • 2. Ministry of Food and Drug Safety
  • 3. University of South Florida
  • 4. University of Chicago
  • 5. St. Jude Children's Research Hospital

Description

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.

Data availability

The RNA seq data generated in this study have been deposited in the GEO database under accession code GSE213138. All data used to generate graphs in this study are provided in the Supplementary Information and Source Data files. Source data are provided with this paper.

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Additional details

Identifiers

DOI
10.1038/s41467-023-44465-8
Other
oai:uchicago.tind.io:10636

Funding

National Institutes of Health
R01NS090993
National Institutes of Health
R01AG030142
National Institutes of Health
R35CA231620
National Institutes of Health
R35CA197450
National Institutes of Health
R01AG045571
National Institutes of Health
R56AG045571
National Institutes of Health
R01AG067781
National Institutes of Health
U19AG073153
National Institutes of Health
P30AG072977
National Institutes of Health
P30AG13854
National Institutes of Health
R01NS124783
National Institutes of Health
L40CA231423
McKnight Brain Research Foundation

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Neurology