The cause of certain genetic form of Parkinson’s disease has been confirmed by a team of international researchers as part of a 7-year research effort. The researchers have also identified potential pharmacological treatments that could be effective against the disease.
The research was led by Prof. Rejko Krüger, of the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg. The researchers studied patient-based cell cultures in the lab and found a protein known as DJ-1 is essential for keeping nerve cells fully functional.
Patients who are unable to produce sufficient levels of the DJ-1 protein, or who produce defective DJ-1 proteins, will go on to develop degenerative diseases such as Parkinson’s disease. The researchers identified one such error in the DJ-1 production process known as splicing and showed that this defect led to the development of a certain form of Parkinson’s disease.
“In the patients, an essential tool for the assembly of the protein DJ-1 fails to dock properly,” said Krüger. “In scientific terms, we call that exon skipping. As a result of this defect, the protein doesn’t get built at all.” This was the first time that researchers had demonstrated how an error in the production of DJ-1 could lead to the development of Parkinson’s.
The researchers obtained skin cells from 800 patients diagnosed with Parkinson’s disease and 800 healthy patients. The skin cells were reprogrammed into induced pluripotent stem cells (IPSCs) and were then differentiated into nerve cells in the lab. The nerve cells were very similar to those in the brains of patients so could be used to study the clinical features of a patient’s neurons in vitro.
Using those neurons, the researchers were able to determine the cause of a genetic form of Parkinson’s disease that involved a defective PARK7 gene.
The research opens up a new avenue of treatment for Parkinson’s. The researchers have already identified active compounds that could potentially be used as a treatment. Using bioinformatics algorithms developed at the LCSB, the researchers identified two compounds – phenylbutyric acid and RECTAS (RECTifier of Aberrant Splicing) – which when administered together reactivated production of the protein DJ-1 in the lab. Those compounds will now need to undergo clinical trials to determine whether they are effective in vivo and safe to use.
You can read more about the research in the paper – A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson’s disease – which was recently published in the journal Science Translational Medicine. DOI: 10.1126/scitranslmed.aau3960