Molecular Stress in Old Neurons Increases Susceptibility to Neurodegenerative Diseases, Study Finds

Yeo’s team created aged neurons in the lab by using a cell culture approach called transdifferentiation. This technique directly reprograms skin cells from human donors into neurons that appear old at the molecular level.

The team discovered that in comparison with young neurons, old neurons displayed hallmarks of molecular stress, such as halting growth and storing untranslated RNA and proteins in compartments called “stress granules” outside of the cell’s nucleus.

The molecular stress prevented the aged neuron cells from contending with new stress events. “It’s the neuronal equivalent of being so stressed that you catch a cold,” said first author Kevin Rhine, Ph.D., a postdoctoral research fellow in Yeo’s lab.

The researchers also found that:

• Aged neurons took much longer to recover from stress than young neurons, lacked RNA-binding proteins, and failed to make stress-responsive proteins.
• In aged neurons, a protein called TDP-43, which regulates gene expression in the nucleus of young neurons, instead accumulated in the space outside of the nucleus — resembling the state of neurons in people with Alzheimer’s disease, dementia and ALS.

“We think that aged neurons are prioritizing other proteins and forgetting about the stress response and about RNA-binding proteins that keep everything running smoothly,” said Yeo.

Neurodegenerative diseases put an enormous burden on public health. The researchers think the findings could contribute to the development of new therapies to prevent these diseases.The next step is to pinpoint the source of cellular stress in order to keep RNA in a healthy state, according to the researchers.

The study was published in Nature Neuroscience on June 2, 2025.