Gene expression analysis provides a new view of ageing effects on brain

by Lea Udovč

Ljubljana, 1 December - A group of researchers, including Slovenian Jernej Ule, has finalised a comprehensive analysis of gene expression in the brain during ageing. They have analysed 1,800 brain samples to establish that glial cells are exposed the most to the effects of ageing. These cells support the functioning of neurons - the nerve cells in the brain.

Researcher Jernej Ule.
Photo: Anže Malovrh/STA

Researcher Jernej Ule.
Photo: Anže Malovrh/STA

Researcher Jernej Ule.
Photo: Anže Malovrh/STA

Researcher Jernej Ule.
Photo: Anže Malovrh/STA

In the analysis published in the scientific journal Cell Reports (, the researchers analysed brain samples from healthy individuals to find out what changes take place in different types of cells during ageing.

According to Ule, previous studies focused on neurons, as it is mostly these nerve cells that die out in patients suffering from neurodegenerative diseases, such as the ageing-related Alzheimer's and Parkinson's diseases.

Ule's group meanwhile discovered that glial cells get affected the most by ageing, which was a big surprise.

What is special about the analysis is that it examined ten different parts of the brain in order to establish which parts of the brain are affected the most by ageing. It has shown for instance that ageing strongly affects the hippocampus, the part which enables memory and learning, and which gets affected by Alzheimer's.

The analysis is based on data obtained from a collection of post-mortem samples of brain tissue from 480 healthy individuals aged between 16 and 105.

Changes at the cellular and molecular levels in brain tissue take place before a disease develops, which is why one needs to look into the brain of healthy individuals in order to understand early changes, Ule explained.

Only a limited number of samples had been examined earlier, mostly because it is difficult to obtain them and because of the costs related to such studies. This time, a majority of data has been acquired as part of a large separate study conducted by a consortium of different groups in the UK and the US. The data has been obtained for a different purpose, so the study conducted by Ule did not cost much.

Scientists are increasingly making new computer analyses of data that had already been published, to come to new discoveries with low budgets. The principal author of the article is computational biologist Lilach Soreq, who is experienced in machine learning. "Machine learning can notice patterns which scientists are not able to detect because of the massiveness of data," said Ule.

Discovery important for understanding diseases

Similar to neurons, glial cells have regional identities of sorts, which act like postal numbers that decide at the cellular level how to cooperate with different types of neurons. Scientists have established that two types of glial cells - astrocytes and oligodendrocytes - lose a part of their regional identity in the process of ageing, but it is not completely clear how this affects the connections with neurons.

The discovery is important for understanding diseases, as glial cells support neurons. Why their regional identity gets less pronounced and what is the connection with disease are the questions they want to address in the future.

The group is continuing its research in cell cultures by taking stem cells from patients and healthy individuals. They make neurons from patients' cells and glial cells from healthy individuals' cells and grow them together.

"Thus we can see how support cells of a healthy individual can keep alive neurons of a patient, which would otherwise die in a culture. We can see how connections between different types of cells work, how they maintain one another, perhaps even harm one another, and how this is connected with complexes between proteins and RNA," Ule explained.

Connections between proteins and RNA frequently cause neurodegenerative diseases

In the UK, Ule heads a laboratory at the Francis Crick Institute and the Department of Molecular Neuroscience of the UCL Institute of Neurology. Since earning a PhD degree he has been mainly researching connections between proteins and RNA molecules.

As he explained, RNA molecules were initially the least studied segment as molecular biology started to develop, because they were perceived as a passive intermediary which transmits information from genes to proteins, which are the final product of genes. Now it seems that the balancing of gene expression actually takes place on the level of RNA molecules, which is especially important for genes, says Ule.

It has turned out that the connections between proteins and RNA are frequently a cause of neurodegenerative diseases, primarily motor neurone diseases (MND). Interesting bio-physical processes take place at the level of these connections, with proteins and RNA forming microscopic drops in cells.

Even if these proteins are isolated from a cell, they frequently start forming drops in water, in a way similar to when oil is added to water. In diseases, these drops get transformed into solid forms, which cells try to get rid of. The affected cells are not able to do so, which probably contributes to neurons dying.

Scientists are currently trying to find out what keeps a healthy dynamics of protein drops and how to keep such a healthy dynamics of cells.

There would be no evolution without diseases

While Ule developed the CLIP method to determine connections between proteins and RNA molecules while studying in New York, he is also developing CLIP and similar methods in order to "get answers to the questions of how cells work and how to preserve their healthy functioning".

"I'm primarily interested in what this data and research can tell us about life, how we have arrived to this point, how the changes in our evolution reflected on the functioning of our cells and how this helps us understand diseases," Ule said.

He has noticed that the modern world is focused too much on "the last step", on treatment of each individual disease. "But the understanding of basic processes shows that different diseases have some common points and that cells maintain weak balances, which means that treatment of one process can sometimes disrupt some other balance."

Cell processes in diseases are also closely connected with the evolution. "If we were perfect machines, without any disease, it would be a sign that the evolution has stopped and that we are not developing further. Diseases give us signals that we are still developing and that we are taking new directions as a species," Ule stressed.

European style in science suits him well

Ule frequently visits Slovenia to keep in touch with different Slovenian researchers. He calls such work between groups the "European style in science," which suits him well.

In the US, an individual group usually takes over an entire project and then competes with other groups, while Europe usually supports small groups which are solving research problems together.

He finds Slovenia especially appealing because people here have very good basics. Topics of research are being developed for a long time, which results in a more profound knowledge. In large research centres one is under strong pressure to always be in the forefront, which means that topics need to be changed frequently".

About Jernej Ule

Ule graduated at the University of Ljubljana in 1999. He earned a PhD degree at the Rockefeller University in New York in 2004, where he stayed as a post-doctoral researcher until June 2006. After that, he established his own research group at the MRC Laboratory of Molecular Biology in Cambridge in the UK, working there until 2013.

In April 2013, he moved to the University College London (UCL), where he works as a professor at the Department of Molecular Neuroscience. His research group works at the Francis Crick Institute and the UCL Institute of Neurology. His research is financed primarily by the European Research Council and the British biomedical research charity Wellcome Trust.