The Neuronal Resiliency Project at the McDonnell Genome Institute (MGI) is a pioneering effort aimed at uncovering why certain neurons are more resilient to damage in neurodegenerative diseases like Alzheimer’s, Parkinson’s, and ALS. By understanding these mechanisms of resilience, we hope to unlock new therapeutic strategies that can slow or prevent the progression of these devastating conditions.
Aging is the largest risk factor for neurodegenerative disease, with nearly 50% of people over the age of 85 developing some form of dementia. Although extensive genetic research has revealed over 100 associations with Alzheimer’s, fewer than 1% of cases are caused by a direct genetic mutation. This suggests that environmental stressors—such as diet, toxins, and mental stress—play a critical role in the accumulation of damage to neurons. But intriguingly, not all neurons are affected equally, and understanding this selective resilience is at the heart of the Resiliency Project.
Our Approach to Understanding Neuronal Resilience
The Resiliency Project takes a large-scale, multi-disciplinary approach to study selective neuronal vulnerability. Here’s how it works:
- Cell Models: We use over 250 induced pluripotent stem cell (iPSC) lines, each with mutations linked to neurodegenerative diseases.
- Neuron Types: These iPSCs are differentiated into four key neuron types to reflect the different regions of the brain impacted by disease.
- Environmental Stressors: We expose these neurons to approximately 10 different stressors—such as oxidative stress and nutrient deprivation—to replicate the conditions neurons face during aging.
- Omics-Driven Analysis: Using advanced multi-omic technologies, we analyze how these neurons respond to stress, examining their transcriptomes, proteomes, and cellular structures to identify resilience pathways.
With over 10,000 samples generated from this effort, the Resiliency Project is leveraging MGI’s cutting-edge infrastructure to analyze these vast datasets and draw insights into how some neurons manage to withstand damage, while others fail.
At the end of the day, we want to compare fingerprints between a mutant, disease-susceptible neuron and one that’s resistant, and ask, what are the differences? This could lead us to new drug targets and treatments.
Jeff Milbrandt, MD, PhD
Pushing the Boundaries of Personalized Medicine
The insights gained from the Resiliency Project are laying the groundwork for the future of personalized medicine. By identifying the pathways that promote neuronal resilience, we can explore new avenues for drug development and therapeutic interventions. These discoveries could not only help prevent or delay the onset of neurodegenerative diseases but also provide broader insights into aging and cellular stress.
At MGI, we are committed to pushing the boundaries of what’s possible in genomic research and disease treatment. The Resiliency Project exemplifies how we are combining our expertise in multi-omic technologies, large-scale data analysis, and cutting-edge research infrastructure to tackle some of the most pressing challenges in medicine today.
Our work is only possible with the collaboration of researchers, scientists, and partners who share our vision for the future of healthcare. Together, we are building a future where personalized medicine transforms the way we understand and treat disease, bringing us closer to healthier aging and improved quality of life for all.
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