DISE - A universal kill code in health and disease

About This Grant

SUMMARY Death induced by Survival Elimination (DISE) is a powerful cell death mechanism in which a class of short RNAs (sRNA) specifically targets a network of genes critical for cell survival in a miRNA-like fashion. G-rich 6mer containing sRNAs kill by targeting C-rich seed matches enriched in the 3'UTR of survival genes (SGs). The kill code is found in certain tumor suppressive miRNAs and it developed over at least 800 M years. Interestingly, we noticed that in tumor bearing animals treated with these toxic sRNAs, while tumors slowed down in growth, normal tissue were not affected. We proposed that at least four different mechanism ensure that normal tissues are protected from DISE. These include global downregulation of miRNAs in all cancers compared to normal tissue, most of which carry nontoxic AU-rich seeds and an upregulation of the targeted SGs in all cancers (new preliminary data in this proposal). We wondered what would happen if the DISE mechanism became overactive and/or the protection against it was lost. Would this result in pathology in affected tissues? With this important question in mind we ventured into neurodegenerative diseases. We found evidence for toxic sRNAs to contribute to Huntington’s disease (HD). Another interesting link we found was with aging during which many tissues including the brain lose expression of abundant nontoxic miRNAs in part we posit to protect themself from endogenous toxic sRNAs. This resulted in a fundamental hypothesis that many neurodegenerative diseases have a toxic RNA component and that a gradual age related loss of protective miRNAs in the brain is one reason that these diseases often have decades of symptom free live before the onset of symptoms. This led to a recent study in which we provided first evidence that DISE contributes to Alzheimer's disease (AD). Consistent with our hypothesis for major neurodegenerative diseases it has been reported that when pathology occurs cancer incidence rates go down consistent with an overactivity of the anti-cancer mechanism. This was shown for HD and Spinal-Bulbar Muscular Atrophy (SBMA), AD, Parkinson's disease and Amyotrophic Lateral Sclerosis (ALS). Based on these data we propose this central hypothesis: Normal tissues are protected from DISE by high amounts of protective miRNAs, expression of which gradually declines during aging making tissues less resilient to a number of stressors causing tissue degeneration. Cancer and many degenerative diseases are therefore two sides of the same coin and in order to understand and eventually treat either of these major diseases the two sides and how they affect each other have to be better understood. In this proposal we will study fundamental mechanisms that allow certain cells to be eliminated while others being protected from DISE and assess what happens when that protection is lost either during aging or by eliminating protective miRNAs. This will be tested in four specific aims: Aim 1: Determine whether the kill code is universal or specific for different cancers and their originating tissues. Aim 2: Identify mechanisms that protect normal cells from DISE. Aim 3: Determine the effects of modulating DISE in AD. Aim 4: Explore changes in DISE sensitivity during aging.