Research Shows That Key Molecules in Nerve Cells are Preserved for a Lifetime

Most human nerve cells last a lifetime without renewing themselves. A property that is reflected in the components of the cells, some of which last as long as the organism itself. New research by Martin Hetzer, molecular biologist and President of the Institute of Science and Technology Austria (ISTA), and colleagues discovered RNA, a typically volatile molecule, in the nerve cells of mice that remain stable for a lifetime. These findings, published in the journal Science, help to unravel the complexity of brain ageing and related diseases.

Knowledge of How Nerve Cells Function Over Time is Important for Understanding Neurodegenerative Diseases

Hetzer is fascinated by the biological mysteries surrounding the ageing processes in organs such as the brain, heart and pancreas. Most of the cells that make up these organs are not renewed throughout a person’s lifetime. The nerve cells (neurons) in the human brain, for example, can be as old as the organism, even up to more than a century, and must function for a lifetime. This remarkable age of neurons could be an important risk factor for neurodegenerative disorders such as Alzheimer’s disease. Crucial to understanding this type of disease is a deeper understanding of how neurons function and maintain control over time. This may open up the possibility of therapeutically counteracting the ageing processes of these specific cells.

The latest joint publication by Hetzer, Tomohisa Toda from Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), who is also associated with the Max Planck Center for Physics and Medicine, Erlangen, and colleagues provides new insights into this previously little-studied area of complicated mechanisms. The study shows for the first time in mammals that RNA – an essential group of molecules that is important for various biological processes within the cell – can persist throughout life. The scientists identified specific RNAs with genome-protecting functions in the nuclei of mouse nerve cells that remain stable for two years, i.e. for a lifetime. These results underline the importance of long-lived key molecules for maintaining the function of a cell.

Stable DNA, Transient RNA

The inside of cells is a very dynamic place. Some components are constantly renewed and updated, others remain the same throughout their entire life. It is like a city in which the old buildings mix with the new. For example, the DNA in the cell nucleus – the heart of the city – is as old as the organism itself. The DNA in our nerve cells is identical to the DNA in the developing nerve cells in the womb. In contrast to stable DNA, which is constantly being repaired, RNA, especially messenger RNA (mRNA), which forms proteins on the basis of DNA information, is characterized by its transience. However, the cellular scope extends beyond mRNA to a group of so-called non-coding RNAs. They do not turn into proteins, but have specific tasks that contribute to the overall organization and function of the cell. Interestingly, their lifespan has remained a mystery. Until now.

Long-Lived RNAs in Different Cell Types in the Brain

Hetzer and Co. set about unraveling this mystery. To do this, they “labeled” RNAs in the brains of newborn mice. For this labeling, the researchers used RNA analogs – structurally similar molecules – with small chemical hooks that click fluorescent molecules onto the actual RNAs. This enabled efficient tracking of the molecules and informative microscopic snapshots at any point in the mice’s lives.

Surprisingly, the first images showed the presence of long-lived RNAs in different cell types in the brain. The researchers had to break down the data further to identify the RNAs in the nerve cells. Working with Toda’s lab allowed them to sort through this chaos in mapping the brain. Working together, the researchers were able to focus exclusively on long-lived RNAs in neurons. They quantified the concentration of these molecules throughout the life of a mouse, studied their composition and analyzed their locations.

While humans have an average life expectancy of around 70 years, the typical life expectancy of a mouse is 2.5 years. After one year, the concentration of long-lived RNAs was slightly reduced compared to newborns. But even after two years, they were still detectable, indicating a lifelong persistence of these molecules.

Long-Lived RNAs Could Play a Role in the Permanent Regulation of Genome Stability

The scientists also demonstrated that long-lived RNAs play an important role in the longevity of cells. They found that long-lived RNAs in neurons consist of mRNAs and non-coding RNAs and accumulate near the heterochromatin – the densely packed region of the genome that normally harbors inactive genes. They then investigated the function of these long-lived RNAs.

In molecular biology, the most effective way to achieve this is to reduce the molecule of interest and then observe its effects. As their name and the experts’ previous experiments suggest, these long-lived RNAs are extremely stable. The scientists therefore applied an in vitro approach (outside a living organism) using neuronal progenitor cells, i.e. stem cells capable of giving rise to nerve cells, including neurons. This model system allowed them to effectively interfere with these long-lived RNAs. A reduced amount of long-lived RNAs led to problems in heterochromatin architecture and the stability of the genetic material, ultimately affecting the viability of the cells. In this way, the important role of long-lived RNAs for the longevity of cells could be clarified.

The study shows that long-lived RNAs could play a role in the permanent regulation of genome stability. According to Hetzer, the lifelong maintenance of the cell during ageing involves an extended lifespan of key molecules such as the long-lived RNAs they have just identified. However, the exact mechanism is still unclear. Together with as yet unidentified proteins, long-lived RNAs probably form a stable structure that somehow interacts with heterochromatin. Future research projects in Hetzer’s lab are aimed at finding these missing links and understanding the biological properties of these long-lived RNAs.

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