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

Abstract

Background: 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 recently discovered powerful cell death mechanism mediated by short (s) RNAs including micro (mi) RNAs acting through the RNA induced silencing complex (RISC). G-rich 6mer seed sequences in the sRNAs (position 2-7) target hundreds of C-rich seed matches in genes essential for cell survival resulting in the simultaneous activation of multiple cell death pathways. The RISC of most cells is occupied by miRNAs with nontoxic 6mer seeds, which may protect them from DISE by blocking loading of toxic sRNAs. However, during aging when miRNA expression decreases, toxic sRNAs may enter the RISC more readily leaving cells primed for DISE. Whether DISE contributes to neuronal loss in a neurodegenerative disease such as AD has not been evaluated. Methods: Using Ago precipitation and RNAseq (Ago-RP-Seq) combined with SPOROS, a recently developed bioinformatics pipeline to analyze small RNAseq data with respect to 6mer seed toxicity, we analyzed RISC bound sRNAs (R-sRNAs) in in vitro models and in the brains of multiple in vivo AD mouse models, aged mice, and AD patients. Results: We find that in in vitro cell line studies, in mouse models that show neurodegeneration, and in the aging brain R-sRNAs shift to more toxic seeds. In contrast, in cells that survived in post-mortem brains of AD patients and the brains of "SuperAgers", individuals over age 80 who have superior memory performance, R-sRNAs shift to more nontoxic seeds, supporting a protective function of miRNAs. Conclusion: Our data provide first evidence of a contribution of DISE to the neurotoxicity seen in AD suggesting that increasing the levels of protective miRNAs in the brain or blocking the activity of toxic R-sRNAs could lead to a novel way of treating the disease.

Contribution of 6mer seed toxicity to HIV-1 induced cytopathicity

“…Our data suggest both an involvement of a v-miRNA as well as a contribution of cellular R-sRNAs to HIV induced cell death. Such a shift of cellular R-sRNAs to more toxic seeds may prime cells for DISE similar to other systems we have tested recently (47, 49).…”

“…In addition to direct cytotoxic effects of viral RNAs on infected cells, infection with HIV may also shift the ratio of cellular R-sRNAs to more toxic seeds essentially priming the cells to undergo DISE. This effect was recently found in ovarian cancer cells sensitive to chemotherapy compared to treatment resistant cancer cells (47) and in brain cells from Alzheimer’s disease patients compared to normal controls (49).…”

“…Such a shift of cellular R-sRNAs to more toxic seeds may prime cells for DISE similar to other systems we have tested recently (47,49). Assessing this was complicated by a profound increase in viral infection in cells lacking any of the miRNA processing enzymes, Drosha, Dicer or XPO5.…”

CD95/Fas ligand mRNA is toxic to cells through more than one mechanism

“…Both the overall 6mer seed viability of all sequences or differentially expressed sequences can then be determined. We found that small shifts in the 6mer seed viability of Ago bound sRNAs can predict cellular responses to toxic stimuli [14][15][16].…”

“…We recently provided evidence to suggest that in a number of models it is the balance of all RISC bound reads with toxic versus nontoxic seeds that can determine cell survival [14][15][16]. Using SPOROS we therefore analyzed the 6mer seed viability of reads that were significantly enriched or depleted (adjusted p-value < 0.05) in the RISC of d.k.o cells infected with the various CD95L mutants.…”