Aging affects the way neurons, or nerve cells, handle stress, making them more vulnerable to damage. This can lead to neurodegenerative diseases like Parkinson’s, as highlighted by a recent study analyzing cells and brain tissue.
Kevin Rhine, PhD, the lead author and postdoctoral researcher at UC San Diego’s Sanford Stem Cell Innovation Center, described aging neurons as being comparable to someone so overwhelmed that they end up catching a cold.
The paper, titled “Neuronal aging causes mislocalization of splicing proteins and unchecked cellular stress,” was published in Nature Neuroscience.
Aged neurons struggle with stress response
With age, the likelihood of developing Parkinson’s and similar neurodegenerative conditions increases. These diseases pose a considerable public health challenge, but the specific changes in aged neurons remain somewhat of a mystery.
To uncover more, Yeo’s team sourced skin cells from healthy older individuals and reprogrammed them into neurons while retaining signs of aging. They compared these cells to brain tissue from both humans and mice.
The analysis revealed changes in the activity of over 4,000 genes in aged neurons. While genes for RNA-binding proteins still existed, the actual proteins were found in lower amounts. Many had relocated from the nucleus—where they typically function—into the cytoplasm, the cell’s fluid part.
Yeo noted that aged neurons seem to be prioritizing different proteins and neglecting their stress responses. Without sufficient RNA-binding proteins, the neurons can’t accurately edit genetic instructions.
Key protein absent from stress granules
One protein behaving unusually in the study was TDP-43. Like some others associated with neurodegenerative diseases, TDP-43 can create toxic clusters that harm neurons. This protein is typically found in excess in individuals with amyotrophic lateral sclerosis (ALS), but it has also been linked to Parkinson’s.
Under stress, certain proteins usually migrate into stress granules—temporary storage areas in cells that appear during stressful times. However, in aged neurons, these proteins didn’t relocate as they should have, and TDP-43 was absent from these granules, which may explain its tendency to aggregate.
Aging is a significant risk factor for neurodegeneration, and our findings reveal that aging disrupts RNA metabolism in neurons both mechanistically and functionally.
Old neurons could already be under persistent stress, which hampers their normal stress response. This ongoing stress also impacts other cellular processes, like ubiquitylation, which is essential for removing damaged proteins or unnecessary material from cells.
To ensure their lab-grown aged neurons truly represented real aging, the researchers examined brain tissue from individuals aged 30 to 50 and 80 to 90. The older tissue showed reduced RNA-related pathways, especially for RNA-binding proteins, aligning with their findings in aged neurons.
Moreover, in older brain tissue, TDP-43 was often found mislocated in the cytoplasm, similar to what they observed in the aged neurons, indicating that these neurons may genuinely reflect key aspects of aging in the human brain.
The researchers summarized that aging fundamentally destabilizes RNA metabolism in neurons, emphasizing its role as a primary risk factor for neurodegeneration.
