Molecular stress makes old neurons vulnerable to neurodegenerative diseases

As the global population ages, the risk of developing neurodegenerative diseases such as dementia, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS) continues to rise. But the molecular mechanisms behind the deterioration of brain cells have remained elusive.

Now, a new study by University of California San Diego School of Medicine researchers has found that old neurons have unique defects resulting from molecular stress that make them especially vulnerable to neurodegeneration.

Aging has been a black box for a long time. Nobody is really sure what an aged neuron looks like, how it behaves, or how it's different from a young neuron."

Gene Yeo, Ph.D., corresponding author, professor in the Department of Cellular and Molecular Medicine at UC San Diego School of Medicine, and director of the university's Center for RNA Technologies and Therapeutics and the Sanford Stem Cell Innovation Center at the Sanford Stem Cell Institute

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 will be published in Nature Neuroscience on June 2, 2025.