As the global population ages, the risk of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, dementia, and ALS continues to climb. However, the precise molecular causes behind the decline of brain cells have remained unclear—until now.
A new study by researchers at the University of California San Diego School of Medicine has uncovered unique molecular defects in aged neurons that leave them especially vulnerable to neurodegeneration.
Using a cutting-edge technique called transdifferentiation, the team converted human skin cells directly into neurons that exhibit signs of aging at the molecular level. Comparing these aged neurons to younger counterparts, the scientists observed hallmarks of molecular stress, including halted growth and the accumulation of untranslated RNA and proteins within “stress granules” outside the cell nucleus.
“This is like neurons being so overwhelmed by stress that they’re unable to respond properly—similar to how you might catch a cold when you’re already exhausted,” explained Kevin Rhine, Ph.D., first author and postdoctoral fellow in the lab.
Key findings included:
- Aged neurons required significantly longer to recover from stress and lacked critical RNA-binding proteins necessary for proper cellular function.
- The protein TDP-43, essential for regulating gene expression in young neurons’ nuclei, was mislocalized outside the nucleus in aged neurons—a pattern also seen in brains affected by Alzheimer’s, dementia, and ALS.
- Researchers suggest aged neurons shift focus away from maintaining stress responses and RNA regulation, leading to cellular dysfunction.
“These insights highlight how molecular stress impairs the resilience of aging neurons, potentially opening doors for novel therapies to combat neurodegenerative diseases,” said Yeo, the study’s lead investigator.
The team’s next goal is to identify the root causes of cellular stress and develop strategies to maintain healthy RNA function, with the hope of slowing or preventing neurodegeneration that affects millions worldwide.
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