The distance that the small RNA molecules travel through nerve cells, or neurons, is comparable to a person circling the globe. The longest neurons in the human body are located in the lower back, and it is from here that the RNA journeys along highly branched structures that can extend all the way down to the toes. This is how neurons control our leg and foot muscles over long distances. If the RNA transport system stops working properly, it can no longer provide key information needed to make proteins. As a result, neurons die and muscle control ceases to be possible – like in neurodegenerative diseases such as amyotrophic lateral sclerosis.
Scientists long thought that certain sequences within the RNA played a major role in transport of the molecules. But now, in a new study by the Local RNA Metabolism in Neurons and Neurodegeneration Lab, an independent research group at the Berlin Institute for Medical Systems Biology (MDC-BIMSB) of the Max Delbrück Center, researchers have discovered that the crucial factor in the RNA reaching its final destination is actually its life span. The team, led by Prof. Marina Chekulaeva, recently published its findings in the journal “Molecular Cell.”
Many RNAs don’t need a zip code
To study RNA transport, the researchers first had to separate the cell body (soma) from the cell extensions (neurites). This was done by combining a simple method that the group developed in 2017 with a technique for determining the life span of RNA molecules. “That’s how we found out that the average life span of RNA in the neurites is significantly longer than that in the soma,” explains Dr. Inga Lödige, a biochemist and one of the study’s co-authors. No study had examined this aspect before.
In retrospect, the finding that the longer RNA lives, the farther it can travel to distant locations in the cell, did not seem all that significant to the team. But for the researchers, this observation represented a paradigm shift. “Until now, we had assumed that all RNA molecules require a ‘zip code’ to reach distant parts of a cell,” Chekulaeva explains. Ever since the discovery of the first RNA zip code nearly 30 years ago, scientists have been searching for other zip codes, but to date only a few have been found. “Our work provides an explanation for this,” she says. “A large proportion of the RNAs that are transported don’t need a zip code at all. What is critical to transport success is a long life span.”
“Typically, RNAs have a short life span of only a few hours,” explains Artem Baranovskii, who is also a co-author of the study. “Certain RNA sequences act like built-in timers, thus ensuring that the RNAs degrade quickly.” These elements are absent in RNAs located in the neurites. Interestingly, these are the RNAs that are crucial to basic cellular functions, the bioinformatician explains. By using genetic tricks to alter their life span, the researchers were able to control whether the RNA reaches far-away neurites. A long half-life, he says, ensures that it is always available in the neurites of distant cells.
“Our results show that we need a new model that explains RNA transport in neurons,” Chekulaeva says. “It appears that the cell’s delivery system doesn’t depend so much on specific signals as on general RNA features that make sure important messages reach the right place in the cell.”
Text: Inga Lödige
Inga Lödige et al. (2023): “mRNA stability and m6A are major determinants of subcellular mRNA localization in neurons” in: Molecular Cell,