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Biologists discover an unusual feature of neuronal aging

Neurons of 19-month-old mice (bottom row) have much higher oxidative stress levels than those of 9-week-old mice (top row). Lipofuscin, a molecule associated with aging-related oxidative stress, appears in red. Credit: Hyeseung Lee

As we get older, neurons in our brains can be damaged by free radicals. MIT biologists have now discovered that this type of damage, called oxidative stress, produces an unusual stacking of short RNA extracts in some neurons.

The researchers believe that this accumulation of RNA, which could be a marker of neurodegenerative diseases, can reduce protein production. Researchers have observed this phenomenon in the brains of mice and humans, particularly in a part of the brain called the striatum, a site involved in diseases such as Parkinson's disease and Huntington's disease.

"The brain is very metabolically active and, over time, it causes oxidative damage, but it affects some neurons more than others," says Christopher Burge, professor of biology at MIT. "This phenomenon appears to be an unrecognized consequence of oxidative stress, which impacts hundreds of genes and could influence the translation and regulation of RNA globally."

Burge and Myriam Heiman, an associate professor of brain and cognitive science in the Latham family, are the lead authors of this article. Cell reports. Peter Sudmant, a former MIT postdoc, is the main author of the newspaper, and the postdoc Hyeseung Lee and former postdoc Daniel Dominguez are also the authors.

A mysterious discovery

For this study, the researchers used a technique developed by Heiman that allows them to isolate and sequence the messenger RNA of specific cell types. The messenger RNA contains instructions for the construction of proteins in cellular organelles called ribosomes, which read the mRNA and translate the instructions into proteins by chaining the amino acids in the correct order.

The Heiman technique involves labeling the ribosomes of a specific type of cells with a green fluorescent protein. So, when a tissue sample is analyzed, researchers can use the fluorescent marker to isolate and sequence RNA from these cells. This allows them to determine which proteins are produced by different types of cells.

"This is particularly useful in the nervous system where different types of neurons and glial cells are closely related, if you want to isolate the mRNAs of a particular cell type," says Burge.

In separate groups of mice, the researchers labeled ribosomes from D1 or D2 spiny projection neurons, which make up 95% of the neurons present in the striatum. They labeled these cells in younger mice (6 weeks old) and 2 year old mice, which is roughly equivalent to 70 or 80 year old males.

The researchers had planned to look for differences in gene expression between these two types of cells and to explore their impact on age. "These two types of neurons are involved in several age-related neurodegenerative diseases, so it's important to understand how normal aging affects their cellular and molecular properties," Heiman said.

To the surprise of the researchers, a mysterious result appeared: in the D1 neurons of aged mice (but not the neurons of young mice or the D2 neurons of aged mice), they found hundreds of genes expressing that ## EQU1 ## 39, a short fragment of the original sequence of mRNA. These fragments, known as 3-untranslated regions (UTRs), were stuck to ribosomes, preventing ribosomes from assembling normal proteins. "Although these RNAs were previously observed, the magnitude and specificity of the cell type associated with age were truly unprecedented," said Sudmant.

The 3 'UTR extracts appeared to come from about 400 genes with a wide variety of functions. Meanwhile, many other genes were completely unscathed.

"Some genes are quite normal, even in older D1 neurons – this phenomenon has a gene-specific appearance that is quite interesting and mysterious," Burge said.

The results led the researchers to explore the possible role of oxidative stress in this accumulation of 3 UTR. Neurons burn a lot of energy, which can produce free radicals as by-products. Unlike many other types of cells, neurons are not replaced. It is therefore thought that they are susceptible to the damage accumulated by these radicals over time.

The MIT team found that activation of oxidative stress response pathways was higher in D1 neurons than in D2 neurons, suggesting that they are actually undergoing more oxidative damage. The researchers propose a model for the production of 3 isolated UTRs involving an enzyme called ABCE1, which normally separates ribosomes from mRNA after translation. This enzyme contains clusters of iron and sulfur that can be damaged by free radicals, making it less effective at removing ribosomes, which then remain blocked on the mRNA. This leads to cleavage of RNA by a mechanism that works upstream of blocked ribosomes.

"The sending of neural signals takes a lot of energy," says Burge. "Over time, this causes oxidative damage and, in our model, one of the proteins that ends up being damaged is ABCE1, which triggers the production of 3" UTR. "

RNA build-up

The researchers also found the same accumulation in most parts of the human brain, including in the frontal cortex, which is highly metabolically active. They have not seen it in most other types of human tissue, with the exception of liver tissue, which is exposed to high concentrations of potentially toxic molecules.

In human brain tissue, researchers found that the amount of 3 UTR gradually increased with age, which corresponds to the proposed model of progressive injury by oxidative stress. The findings and model of the researchers suggest that the production of these 3 UTR involves the destruction of normal mRNAs, thereby reducing the amount of protein produced from the affected genes. This accumulation of 3 UTR with ribosomes stuck to them can also prevent ribosomes from producing other proteins.

According to Burge, it remains to be seen exactly what effect it would have on these neurons, but it is possible that this type of cell damage combines with genetic and environmental factors to produce a general decline in cognitive abilities or even neurodegenerative conditions such as Parkinson disease. disease. In future studies, the researchers hope to further explore the causes and consequences of 3 UTR accumulation.

Explore further:
Revisiting the center of protein synthesis

Journal reference:
Cell reports

Provided by:
Massachusetts Institute of Technology

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