The search for causes of neurodegenerative diseases

8 February 2022

In spring 2021, the Faculty of Biology at Johannes Gutenberg University Mainz (JGU) was lucky to acquire a specialist in the field of neurodegenerative disorders – Professor Dorothee Dormann. A cell biologist and biochemist by training, she is an expert in identifying the molecular processes that underlie conditions such as Alzheimer's disease and has already won several awards for her research.
 

When she talks about her work outside her research community of specialists, Professor Dorothee Dormann avoids using technical terminology as far as possible. This is rather difficult in her field. But even so, she is able to provide us with a very clear description of what it is she actually does. "We are interested in the malfunctions in the nerve cells of patients suffering from neurodegenerative disorders and what causes these cells to die," explains Dormann. Her team focuses on investigating amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two conditions that share certain features with Alzheimer's disease, but occur more rarely and typically at a younger age. "Our approach is to look at the molecular processes to track down the causes of these diseases. This involves generally applicable principles of cellular biology."

Her research is all about proteins doing things they are not supposed to do. Dormann gives a couple of examples: "One phenomenon that was discovered some time ago is an aggregation process that occurs in certain unfolded protein regions. Molecules accumulate to form droplet-like assemblies." This initially happens in just a few neurons but then the effect starts to snowball, spreads to other parts of the brain, and eventually results in the full development of disease. "These droplets separate from other cellular molecules, like oil droplets in water. We call this process phase separation. Normally, cells are capable of preventing protein aggregation of this kind. Now we would like to know how they do this. What makes these molecules accumulate in the first place and what causes their dispersal."

Protein clumps with fatal consequences

Dormann gives another example: "We know that in ALS and FTD, certain proteins accumulate at high concentrations in the neurons. In healthy cells, a specific molecule transports these proteins into the cell nuclei. There they take over important tasks, including the reading of the genetic information. But if this transport system malfunctions, the proteins remain in the surrounding cytoplasm." And here they start to form clumps that can have fatal consequences.

"Once we understand exactly how these processes work and if we would find a way to boost the transport of these proteins into cell nuclei, we would have made significant progress towards finding a treatment," she explains. "This could be the case not only for ALS and FTD, but also for Alzheimer's disease. In recent years, we have been able to establish that many of the processes that occur in neurodegenerative conditions are very similar to each other."

Dormann is still a new face in Mainz. She was appointed Professor of Molecular Cell Biology at the Institute of Molecular Physiology of JGU in spring 2021. She previously headed an Emmy Noether Research Group at Ludwig-Maximilians-Universität München (LMU). Now she has more or less completed her move to Mainz, although for the time being her desk is located in the office of her colleague Professor Edward A. Lemke. Her future office and lab space is currently undergoing a complete makeover.

Dormann has gained an outstanding reputation for her research into neurodegenerative diseases. She has made important contributions to the better understanding of ALS and FTD. For this, she has been awarded the Heinz Maier-Leibnitz Prize and the Paul Ehrlich and Ludwig Darmstaedter Prize for Young Researchers. She has also recently won the Alzheimer Research Prize of the Hans and Ilse Breuer Foundation endowed with EUR 280,000. Dormann studied Biochemistry in Tübingen and North Carolina. To study for her doctorate, she first went to The Rockefeller University in New York in 2007 before transferring to LMU.

Excellent research environment at Mainz University

Dorothee Dormann will be continuing her research at JGU with a Heisenberg professorship. She has brought some of the members of her former Munich team with her. "Because of lockdown, the move and looking for a place to live was a little hard," she states. "And, at present, we also can't enjoy university life to the full – which naturally is a pity to all of us."

However, the decision to relocate to Mainz was an easy one for her. "It is the excellent research environment here that is very appealing to me. The Faculty of Biology is undergoing a transition period in which many professorships are newly filled and we can actively participate in what is happening. There are close ties between JGU and the Mainz University Medical Center, and a number of colleagues are investigating molecular processes I'm particularly interested in. I can see a lot of common research interest – also with the Max Planck Institute for Polymer Research, for example." As Adjunct Director of the Institute of Molecular Biology (IMB), Dormann is also in close contact with yet another important research institution on campus. "It's fantastic and a great advantage that I can use the superb core facilities there."

Dormann conducts fundamental research. "We take a reductionist approach and therefore do not need to undertake animal experiments. We primarily work in the lab with test tubes." Here they model the processes in nerve cells without any interfering factors. "The less complex we can make the processes, the easier it makes it for us to understand what causes them."

Research to facilitate early diagnosis

And these causes are at the very heart of research into neurodegeneration, whilst also keeping the practical clinical benefits firmly in mind. "We know that the onset of diseases like Alzheimer's disease, FTD, and ALS is very early, often 10 to 20 years before we are able to diagnose them. For Alzheimer's we now have medications that can hinder or slow down the degenerative processes by countering the aggregation of proteins in cells. But these have so far only been used in clinical trials on symptomatic patients, in which too much damage has already occurred. What we need to do is try to find out more about the very early signs of the disease. So our challenge is to identify so-called biomarkers that could help us diagnose these disorders at an early stage, prior to symptoms. Then we could provide patients with genuine help." This would concern people between 40 to 45 years of age. In this age group it could well prove possible to stop the progression of the neurodegenerative process before it is able to cause noticeable defects.

"We still do not really know why certain proteins end up accumulating in neurons," admits Dormann. But that is what she hopes to establish through her research. Once the researchers understand the mechanisms on the molecular level, they have the opportunity to develop diagnostic and therapeutic procedures that could help counteract neurodegeneration in its earliest stages.