Genetic defect leads to motor disorders in flies

In their study, the research groups looked at a protein called Creld. A study from Bonn recently was able to show that Creld plays an important role in the development of the heart in mammals. “We wanted to know exactly what the protein does,” explains Dr Margret Helene Bülow, a lecturer at the LIMES Institute at the University of Bonn.

To do this, the researchers studied fruit flies of the genus Drosophila, which they had genetically modified so that they cannot form Creld. In the animals, the heart rate was characteristically slowed – a sign of energy deficiency. They also showed severe motor impairment. Mitochondria are responsible for providing energy and their malfunction can lead to the death of nerve cells responsible for motor function in humans. The clinical picture is known as Parkinson’s disease.

“So Creld may play an important role not only in impaired heart function, but also in Parkinson’s disease,” said Dr. Nicole Kucharowski of the LIMES Institute, who along with her colleague Marie Paradis were an important part of the experiments in the study. . “The findings of a recent analysis are consistent with this. It suggests that Creld production is often reduced in Parkinson’s patients.”

But how Creld might be related to Parkinson’s disease was a mystery: The protein isn’t found in mitochondria at all. It can only be detected in a ramified network of tubes that serve to produce different molecules in the cell – the endoplasmic reticulum (ER). How can it interfere with the function of cellular power plants from there?

Pesticides Suspected to Cause Parkinson’s Disease

To find out, the researchers administered small amounts of a pesticide to healthy fruit flies (ie, those that can form Creld). It contains the active ingredient rotenone, which is suspected to cause Parkinson’s disease in humans. Rotenone works directly in the mitochondria by inhibiting an important step in energy production. After application of the pesticide, the flies showed motor impairments comparable to those of the Creld mutants. “We also found that their mitochondria interact with the ER very often,” explains Bülow.

In further experiments, the researchers were able to show that certain classes of lipids are transported from the ER to the mitochondria during this contact. These so-called phospholipids restart the energy production step that is inhibited by rotenone. With the help of the emergency room, the mitochondria try to increase the energy supply in this way. “And the availability of Creld appears to be crucial for this transfer of phospholipids,” emphasizes Bülow. “In flies that cannot form Creld, phospholipids accumulate in the contact sites between ER and mitochondria so that they are not transported to the mitochondria, but accumulate.”

Creld increases energy production in the cell

Creld is therefore important for increasing energy production in the cell. This is consistent with the observation that Drosophila mutants without Creld produce hardly any hydrogen peroxide in their mitochondria – this is a molecule produced as waste during the work of the power plants. Hydrogen peroxide can damage cells. Until now it was thought that it was produced in excessive amounts in people with Parkinson’s or that it was not disposed of adequately. This would gradually poison the nerve cells responsible for motor function.

However, it is possible that another effect could be causing their demise, namely the chronic lack of energy caused by damage to or underproduction of Creld. “This is a dissertation that we now need to investigate further,” said Bülow, a member of the transdisciplinary research space “Life and Health” at the University of Bonn.

The current success is also the result of a successful collaboration. For example, essential parts of the work were carried out at the University of Osnabrück. dr. Julia Sellin, who originally helped set up the study, has also recently moved to Aachen University Hospital. “The collaboration with Prof. Dr. Christoph Thiele from the Cluster of Excellence Immunosensation2 here at the University of Bonn also went extremely well,” says Bülow.

The research was published in scientific progress.