Cracking the Code of Rare Diseases
Blindness, obesity, infertility, extra fingers, kidney problems and more: the rare ciliopathic diseases are serious. Scientists know about 35 of them, but there is still no cure. SDU researcher Narcis-Adrian Petriman wants to change that, and the Novo Nordisk Foundation is supporting him with DKK 11.4 million.
Cilia. We have them in our airways, where they help clear out mucus and dirt, but they’re also found on many cells inside our body, where they help the cells move, sense their environment, etc.
When something goes wrong with these tiny hair-like structures – known as cilia— it can lead to a group of serious diseases called ciliopathies. So far, researchers have identified around 35 of them, including Alström Syndrome, Usher Syndrome, Bardet-Biedl Syndrome, and Nephronophthisis. All ciliopathies are rare.
Even though they share the same underlying cause —defective cilia— the diseases manifest in very different ways. For example, Alström Syndrome is associated with hearing loss, obesity, and insulin resistance. Usher Syndrome affects balance and vision. Bardet-Biedl Syndrome may cause extra fingers or toes and learning disabilities. Nephronophthisis may result in excessive urination and anemia.
Narcis-Adrian Petriman
Graduate of Alexandru Ioan Cuza University in Romania, PhD from the University of Freiburg in Germany, and formerly employed at Aarhus University. From there, Professor Jens S. Andersen recruited him to the Department of Biochemistry and Molecular Biology, where he is currently a postdoc in the “Biomedical Mass Spectrometry and Systems Biology” section. With a grant of DKK 11.4 million from the Novo Nordisk Foundation’s “Hallas-Møller Emerging Investigator Bioscience and Basic Biomedicine” program, Petriman can now launch his research project: “CILIAGATE: How the Cilium Controls the Gating of Its Proteins and Lipids? A Structure-Function Analysis of the Ciliary Transition Zone Superstructure.” Petriman’s education and research have been supported by multiple programs, including ERASMUS, the German Academic Exchange Service (DAAD), the Marie Sk艂odowska-Curie fellowship program, and the Lundbeck Foundation.
Research profile is here
Since rare diseases only affect a small number of people, there is limited funding for research. For the pharmaceutical industry, the market is too small to be profitable, and private and public funding bodies usually focus on more common diseases.
- But rare diseases deserve our attention, too. We need to help the people who suffer from them,” says biochemist and molecular biologist Narcis-Adrian Petriman from the Department of Biochemistry and Molecular Biology. “All known 35 ciliopathies are caused by genetic mutations in cilia-associated genes, and I want to understand those better and find a cure. The Novo Nordisk Foundation is one of the few that actively supports research into rare diseases, and I’m very grateful they’ve chosen to support my research.
The funding from the Novo Nordisk Foundation will support two main objectives: first, to understand what’s happening in the part of the cell where the mutations occur, and second, to attempt to develop molecular prosthetics that can replace the defective components.
Zooming in on the cilia
Cilia are hair-like structures that extend from the surface of a cell. They can help move fluid across the cell surface, aid in cell movement, receive signals from the external environment, and transmit information into the cell.
The point where a cilium emerges from the cell is called the transition zone. It is made up of proteins and acts like a doorman—only allowing certain substances to pass in and out.
When mutations occur in the proteins of this zone, it can lead to one of the rare ciliopathic diseases. This is the area Narcis-Adrian Petriman is investigating by using advanced integrative biochemical and structural biology techniques.
Repair of mutation damage
His hypothesis is that the transition-zone contains special “valves” that can rotate and temporarily open to let, for example, proteins and lipids through.
- No one really knows what goes on in the transition zone. I want to test my hypothesis using cell models and try to uncover the mechanisms at play, explains Petriman.
If the hypothesis holds true, the next step would be to try to repair the mutation damage that occurs in the transition zone and causes the ciliopathies.
Molecular prosthetics
Preliminary data obtained by using protein structure prediction tools indicate that some of the proteins that are making up the transition zone are quite large, but they only use a small part of themselves to preserve the functionality of transition zone. Petriman hopes that it will be possible to replace the large defective protein with just the small healthy segment that preserves its functionality—a kind of molecular prosthetics.
- If we can replace the defective part, we might be able to restore the function of the transition zone and thereby providing treatment strategies to cure the disease, he says.
Petriman’s interest in this specific topic—the transition zone of cilia—started almost by chance. Five years ago, he knew no more about cellular cilia than other fields in structural biology. But when he joined Esben Lorentzen’s research group at Aarhus University’s Department of Molecular Biology and Genetics that was studying cilia structures, he was hooked.
- There’s still so much we don’t know about the structural organization of cilia at molecular level and their role in disease. I want to help change that—for the patients who today lack both treatment and hope, he says.