Unveiling Harmful and Protective Short RNAs Linked to Alzheimer's Disease and Enhanced Memory Skills

 

In a recent study published in Nature Communications, researchers delved into the intricate world of Alzheimer's disease (AD) by exploring the Death Induced by Survival Gene Elimination (DISE) and its correlation with neurotoxicity. The focus was on ribonucleic acid (RNA)-induced silencing complex (RISC)-bound short RNAs (R-sRNAs) and their impact on neuronal survival in AD models.

Background

AD is characterized by poorly understood neurodegeneration, featuring Amyloid Beta (Aβ) plaques, hyper-phosphorylated tau protein (p-tau) accumulation, and multiple cell death pathways. Established connections exist between Aβ42 toxicity, genetic links in familial AD, and the acceleration of deoxyribonucleic acid (DNA) damage due to aging.

In RNA interference (RNAi), micro (mi)RNAs post-transcriptionally regulate gene expression. R-sRNAs with guanine (G)-rich 6mer seeds can activate cell death pathways through DISE. The study aims to uncover how modifying nontoxic miRNAs could potentially be a treatment for AD.

About the Study

The study employed various methods, utilizing mouse and human brain tissues for analysis. Key reagents and antibodies were prepared, and Aβ peptides were synthesized. Cell culture work included generating knockout (k.o.) cells, assessing cell growth and viability, and treating SH-SY5Y (SH) cells with Aurintricarboxylic acid and Enoxacin.

Genetic analysis involved RNA extraction, reverse transcription, and quantitative real-time polymerase chain reaction (PCR). Protein levels and interactions were studied through Western blot analysis, while DNA fragmentation in mouse brains was detected using Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining.

Study Results

The study revealed a crucial role of R-sRNAs in AD, with aging showing a shift towards toxic 6mer seeds, less viable and more likely to induce neuronal cell death through DISE. This shift is linked to reduced production of nontoxic miRNAs by aging neurons. Key enzymes like Dicer and Drosha, essential for miRNA expression, are compromised during AD and aging due to reactive oxygen species and interferons.

Two primary cellular responses to Aβ42 involving RISC activity were identified: cell death/DISE and DNA damage. DISE integrates various cell death pathways, contributing not only to neuronal cell death but also to neurodegeneration by inducing DNA damage. The study suggests a need for further research to understand its full impact on synaptic dysfunction and AD pathology.

The findings propose that the increase in toxic sRNAs and the loss of nontoxic miRNAs during aging might contribute to other neurodegenerative diseases like Parkinson's, Huntington's, and Amyotrophic Lateral Sclerosis (ALS). The study challenges the conventional focus on amyloid and tau in AD treatment, suggesting that enhancing nontoxic miRNA levels could be a more effective therapeutic strategy.

Conclusions

The study offers a fresh perspective on AD, emphasizing the crucial role of R-sRNAs, specifically the ratio of toxic to nontoxic miRNAs, in neuronal survival and neurodegeneration. The shift towards more toxic sRNAs with aging and AD could be attributed to decreases in key miRNA processing enzymes. DISE, involving various cell death pathways, may significantly contribute to AD pathology and extend to other neurodegenerative diseases. The findings challenge the traditional focus on amyloid and tau, proposing a more effective therapeutic strategy centered around enhancing nontoxic miRNA levels.

----------------------------- Journal Reference:

Paudel, B., Jeong, SY., Martinez, C.P. et al. Death Induced by Survival gene Elimination (DISE) correlates with neurotoxicity in Alzheimer's disease and aging. Nat Commun 2024. Weblink: https://doi.org/10.1038/s41467-023-44465-8 

https://www.nature.com/articles/s41467-023-44465-8 

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Aging, Alzheimer's Disease, Amyloid Plaque, Amyotrophic Lateral Sclerosis, Antibodies, Brain, Cell, Cell Culture, Cell Death, DNA, DNA Damage, Dopamine, Drug Discovery, Gene, Gene Expression, Genetic, Guanine, Huntington's Disease, in vitro, Interferons, Knockout, micro, Neurodegeneration, Neurodegenerative Diseases, Neurons, Oxygen, Parkinson's Disease, Pathology, Peptides, Phosphorylation, Polymerase, Polymerase Chain Reaction, Protein, Reagents, Research, Ribonucleic Acid, RNA, RNA Extraction, RNA Interference, RNA Sequencing, RNAi, Sclerosis, Tau Protein, Transcription, Western Blot