Researchers Decode a Puzzling Movement Disorder

They reprogrammed skin cells from patients with a hereditary movement disorder into so-called induced pluripotent stem cells (iPS cells) and obtained functional nerve cells from them. They subsequently decoded how the disease arises.

The so-called Machado-Joseph disease is at the centre of the current Bonn study. This is a disorder of movement coordination which was originally described in inhabitants of the Azores of Portuguese descent and which represents the most frequent dominantly inherited cerebellar ataxia in Germany today. The majority of patients develop gait abnormalities and a series of other neurological symptoms between the ages of 20 and 40. The cause of the disease is a recurring genetic sequence in the ataxin-3 gene which leads to agglutination of the corresponding protein and as a result, the nerve cells in the brain become damaged eventually. Until now, it was not clear why the disease only affects nerve cells and how the abnormal protein agglutination is triggered.

In order to study the disease process on a molecular level, scientists working with the stem cell researcher Professor Oliver Brüstle at the Institute for Reconstructive Neurobiology at Bonn University initially produced so-called induced pluripotent stem cells (iPS cells) from small skin specimens from patients. These induced pluripotent stem cells are cells which are returned to a very early, undifferentiated stage. These „jacks-of-all-trades“ – once obtained – can be multiplied to a nearly unlimited degree and they mature in all cells of the body. In the next step, the team working with Brüstle converted the iPS cells into brain stem cells from which the scientists were able to develop as many nerve cells needed for their investigations.

In particular: Since the nerve cells come from the patients themselves, they have the same genetic changes and can therefore serve as a cellular model of the disease. ”This method allows us to research the disease in the cells that are actually affected and which we otherwise could not access - almost as if we had placed the patient’s brain into the cell culture dish,“ says Doctor Philipp Koch. Together with his colleague Doctor Peter Breuer, Koch electrically stimulated the artificially created nerve cells. In doing so, the researchers were able to show that the formation of the protein aggregates is directly correlated with the electrical activity of the nerve cells. ”The enzyme calpain plays a key role in this; calpain is activated by the increased calcium content of stimulated nerve cells,“ says the biochemist Breuer. ”This newly identified mechanism explains why the disease only affects nerve cells,“ Brüstle points out.; Source: Rheinische Friedrich-Wilhelms-Universität Bonn