BREAKING Medical News! Research Uncovers Short Strands Of Lethal RNAs That Can Kill Brain Cells And Cause Alzheimer!

Medical News: The landscape of medical research is continually evolving, and recent breakthroughs have illuminated a previously unseen connection between RNA interference and Alzheimer's disease. This revelation is poised to redefine our understanding of neurodegenerative diseases, particularly Alzheimer's, which afflicted an estimated 6.7 million individuals in the U.S. in 2023. This Medical News report explores the groundbreaking study conducted by Northwestern Medicine-USA, shedding light on short strands of toxic RNAs and their role in brain cell death and DNA damage associated with Alzheimer's and aging.


Lethal Short  Strand RNAs That Can Kill Brain Cells
 
RNA's Enigmatic Role in Alzheimer's Pathogenesis
The enigma surrounding Alzheimer's disease lies in the progressive loss of brain cells, with the precise events triggering neuron death remaining elusive. The study, spearheaded by Dr Marcus Peter, the Tom D. Spies Professor of Cancer Metabolism at Northwestern University Feinberg School of Medicine, has unraveled a crucial link between RNA interference and Alzheimer's. This research has unveiled short strands of toxic RNAs that contribute to brain cell death and DNA damage, marking a paradigm shift in our understanding of Alzheimer's pathology.
 
Balancing Act - Toxic and Protective Short RNAs
One of the study's key revelations is the delicate balance between toxic and protective short RNAs (sRNAs) in aging brain cells. As cells age, this equilibrium tilts towards the toxic sRNAs, potentially paving the way for the development of Alzheimer's. Notably, the study found that individuals labeled as SuperAgers, aged 80 and above with memory capacities akin to those 20 to 30 years younger, exhibit higher levels of protective short RNA strands in their brain cells.
 
MicroRNAs as Guardians of Neuronal Health
At the forefront of protective sRNAs are microRNAs (miRNAs), acting as cellular guardians. These miRNAs function as sentinels, preventing the entry of toxic sRNAs into the cellular machinery responsible for RNA interference. The study underscores the significance of the decrease in the number of these protective miRNAs with aging, allowing toxic sRNAs to inflict damage on brain cells and potentially contribute to the onset of Alzheimer's.
 
Death Induced by Survival gene Elimination (DISE) Mechanism Unveiled
The study introduces a novel concept known as Death Induced by Survival gene Elimination (DISE), a powerful cell death mechanism mediated by specific sRNAs through the RNA-induced silencing complex (RISC). This mechanism, a form of RNA interference, targets essential survival genes, triggering multiple cell death pathways. The research correlates DISE with neurotoxicity in Alzheimer's disease and aging, providing a potential link between RNA interference and the specific events leading to cell death in neurodegenerative diseases.
 
Molecular Profil ing Unravels Insights
To gain a deeper understanding of these groundbreaking findings, the study employs advanced molecular profiling techniques. The analysis includes mouse models of Alzheimer's, induced pluripotent stem cell-derived neurons from Alzheimer's patients, and the brains of older individuals known as SuperAgers. The results reveal a shift in the balance of toxic and nontoxic 6mer seeds in RISC-bound sRNAs, indicating a potential role of RNA interference in neurotoxicity.
 
Age-Dependent Loss of Protective miRNAs: A Critical Factor
A critical factor highlighted in the study is the age-dependent loss of protective miRNAs, contributing to neurodegeneration. The research observes a reduction in the viability of 6mer seeds in RISC-bound sRNAs in aging brains, rendering neurons more susceptible to DISE-inducing sRNAs. This gradual loss of nontoxic miRNAs over decades could explain the delayed onset of many neurodegenerative diseases, including Alzheimer's.
 
Implications for Treatment - A Paradigm Shift
Perhaps the most promising aspect of this research lies in its potential implications for treatment. The study challenges the predominant focus on reducing amyloid plaque load and preventing tau phosphorylation in Alzheimer's drug discovery. Instead, the researchers suggest that increasing the expression of nontoxic miRNAs or blocking the activity of toxic RISC-bound sRNAs could represent a viable treatment option for various neurodegenerative diseases.
 
Unveiling a Novel Model - RISC as a Central Rheostat
Building on the study's findings, a novel model emerges in which the RNA-induced silencing complex (RISC) functions as a central rheostat, influencing neuronal cell death and DNA damage observed during aging and in Alzheimer's disease. In young, asymptomatic individuals, the RISC is filled with abundant miRNAs, predominantly containing nontoxic 6mer seeds, acting as protectors against toxic sRNAs.
 
The Alzheimer's Connection - Aβ Oligomers and Tau Aggregation
The study suggests that in Alzheimer's patients as they age, Aβ oligomers and/or Tau aggregation may elicit a cellular response leading to the upregulation of endogenous toxic sRNAs. Mechanistically, this occurs through a direct effect of Aβ oligomers or Tau aggregation, potentially culminating in cumulative effects. The findings hint at the moderate but significant contribution of DISE to cell death induced by toxic Aβ42, highlighting its potential role in the neurotoxicity seen in Alzheimer's.
 
Tau's Role in Aβ42 Toxicity and DNA Damage
Interestingly, the study emphasizes the fundamental role of tau in Aβ42 toxicity. While the deletion of tau substantially protects cells from Aβ42-induced cell death, DNA damage caused by Aβ42 treatment appears to be entirely dependent on RISC engagement. This intricate interplay of factors underscores the complexity of neurodegenerative processes.
 
Wider Implications for Degenerative Diseases
The study's implications extend beyond Alzheimer's, suggesting that the age-dependent increase in toxic sRNAs and the gradual loss of nontoxic miRNAs may be at the core of other degenerative diseases affecting the brain. Conditions such as Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS) might share common underlying mechanisms. The study particularly highlights the genetic connection in ALS, where specific genetic mutations may lead to the production of highly toxic sRNAs, contributing to the disease's pathology.
 
Molecular Profiling - Unveiling a New Layer
The study introduces a new layer to our understanding of Alzheimer's pathogenesis by employing molecular profiling at various levels - genomic, transcriptomic, proteomic, and metabolomic. This multi-dimensional approach provides a comprehensive view, suggesting an age-dependent loss of nontoxic and potentially neuroprotective miRNAs alongside the upregulation or presence of toxic sRNAs. The collective interplay of genetic modifiers, mutations, and changes in sRNA dynamics may collectively contribute to the onset and progression of Alzheimer's.
 
Rethinking Drug Discovery in Alzheimer's
The overwhelming focus in Alzheimer's drug discovery has historically revolved around two mechanisms: reducing amyloid plaque load and preventing tau phosphorylation. However, these efforts have yet to yield an effective treatment for Alzheimer's. The study's findings propose an alternative hypothesis - that a high expression of nontoxic miRNAs may protect against neurodegeneration. Therefore, increasing miRNA biogenesis or blocking toxic RISC-bound sRNAs emerges as a potentially transformative treatment approach for various neurodegenerative diseases.
 
Conclusion - A Transformative Era in Neurodegenerative Disease Research
In conclusion, the research has unraveled a previously unknown connection between RNA interference and Alzheimer's disease. The identification of toxic and protective short RNAs, the introduction of the DISE mechanism, and insights from molecular profiling provide a comprehensive understanding of the role of RNA in neurodegenerative diseases. The age-dependent loss of protective miRNAs emerges as a critical factor, offering a new perspective on the delayed onset of symptoms in neurodegenerative diseases. As researchers delve deeper into this intricate realm of molecular biology, the potential for transformative breakthroughs in neurodegenerative disease therapeutics becomes increasingly evident.
 
This research not only marks a significant milestone in Alzheimer's understanding but also sets the stage for a transformative era in neurodegenerative disease research, where RNA-based interventions may hold the key to effective treatments and, ultimately, disease prevention. The journey to unlock the mysteries of the brain continues, with each revelation bringing us closer to a future where neurodegenerative diseases may be treated and, perhaps, one day eradicated.
 
The study findings were published in the peer reviewed journal: Nature Communications.
https://www.nature.com/articles/s41467-023-44465-8
 
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