An international team of researchers led by Professor Rejko Krüger, of Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg have clarified the cause for certain genetic forms of Parkinson’s disease while also identifying possible pharmacological treatments. The team experimented on patient-based cell cultures in the laboratory and now have identified a new combination of active substances with real promise. Next steps include these new targets undergoing clinical trials before they can be used to treat patients. The latest findings were published in the scientific journal Science Translational Medicine.
Lack of Proteins DJ-Causes Illness
DJ-1 actually plays an integral role in maintaining healthy functioning nerve cells. Should the body not be able to produce sufficient levels of DJ-19 then important nerve cells die. What occurs next is the onset of neurodegenerative diseases, such as Parkinson’s disease. The production of these proteins are disrupted or stopped permanently if the genetic blueprint or the production process they encode are defective.
As it turns out the Luxembourg team, joined by Germans, Italians and Americans, identified for the first time the criticality of an error in the production process referred to as ‘splicing’ in the development of at least a particular form of Parkinson’s disease. Professor Krüger explained “ “In scientific terms, we call that exon skipping. As a result of this defect, the protein doesn’t get built at all.” The research result offers an entirely new point of attack for treating this malfunction of protein synthesis with drugs. “This insight fundamentally changes our view of the causes of the disease and presents entirely new possibilities for treatment,” says Dr Ibrahim Boussaad, LCSB scientist and first author of the scientific paper. “We could only gain this new understanding thanks to the skin cells from the patients,” Boussaad emphasized.
PEARL: Program of the Luxembourg National Research Fund (FNR).
This study, known as the Luxembourg Parkinson’s study was first initiated in 2015 and includes a group of 800 Parkinson’s patients and 800 healthy subjects for the control group. The researchers, thanks to donated skin cells taken by small biopsy, could reprogram these cells to actually grow into nerve cells in the lab—in vitro.
As these nerve cells were similar to the neurons in the impacted regions of the donor’s brain, they were leveraged for investigation. Actual reprogramming is the only method to investigate the clinical features of the patient’s neurons in vitro, reported Science Daily. Called “a patient-based in vitro model,” this represents an important step in the progression toward precision medicine.
By employing this method, the team out of Professor Krüger’s office were actually able to pinpoint the cause of the genetic form of Parkinson’s disease in which the PARK7 gene is mutated. Another collaborator and study co-author from Tübingen University Hospital, Professor Thomas Gasser, reported, “We are proud to have been able to contribute our expertise in the reprogramming of patient cells to this stem cell work of our colleagues in Luxembourg.”
LCSB developed precise bioinformatics algorithms facilitating research teams to automate searchers for potential active substances useful for treatment. This approach led to a hit in the form of phenylbutyric acid and RECTAS (RECTifierof Aberrant Splicing). These two active substances administered in combination actually supported in the test tube the actual reactivation of the DJ-1.
Professor Krüger emphasized that, “Only by combining numerous disciplines — from medical practice, to laboratory research, to computer science — could we understand the cause and at the same time identify active substances for a potential treatment,” Prof. Rejko Krüger explains. He adds, “This kind of scientific progress ‘Made in Luxembourg’ is possible because all the necessary disciplines have been unified in Luxembourg for several years now
Professor Rejko Krüger, Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg