Molecular stress makes old neurons vulnerable to neurodegenerative diseases

As the world population ages, the risk of developing neurodegenerative diseases such as dementia, Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS) continues to increase. But the molecular mechanisms behind the deterioration of brain cells remained vague.

Now, a new study by the University of California, San Diego School of Medical Researchers, has found that old neurons have unique defects that result from molecular stress that make them particularly vulnerable to neurodegeneration.

Aging was a black box for a long time. No one is really sure what an elderly neuron looks like, how it behaves or how it is different from a young neuron. ”

Gene Yeo, Ph.D., corresponding writer, Professor in the Department of Cellular and Molecular Medicine at UC San Diego School of Medicine and Director of the University of Technology and Therapeutic Center and the Sanford Stem Cell Institute of Innovation at the Stem Cell Sanford Institute

The YEO team created elderly neurons in the laboratory using a cellular cultivation approach called differentiation. This technique directly reprogrammes skin cells from human donors to neurons that look old at the molecular level.

The group discovered that compared to new neurons, old neurons showed molecular stress features, such as growth inhibition and storing non -translated RNA and protein in apartments called “granules” outside the nucleus of the cell.

Molecular stress prevented the elderly neuron cells from struggling with new stress events. “It is the neuronal equivalent of being so stressful that you get a cold,” said the first writer Kevin Rhine, Ph.D., a postdoctoral researcher in the YEO lab.

Researchers also found that:

• Elderly neurons took a lot more time to recover from stress from young neurons, had no RNA binding proteins and failed to make proteins that respond to stress.
• In elderly neurons, a protein called TDP -43, which regulates gene expression at the core of young neurons, instead accumulates in space outside the core – resembling the condition of neurons in people with Alzheimer’s disease, dementia and als.

“We believe that elderly neurons prioritize other proteins and forget about the response of stress and RNA binding proteins that keep everything running smoothly,” said Yeo.

Neurodegenerative diseases put a huge weight on public health. Researchers believe that the findings could contribute to the development of new treatments to prevent these diseases. The next step is to identify the source of cell stress in order to keep RNA in healthy condition, according to researchers.

The study will be published in Neuroscience On June 2, 2025.