While investigating links to Gaucher disease — a rare genetic condition with strong ties to Parkinson’s — researchers collaborating across three National Institutes of Health (NIH) centers reported finding a drug molecule potentially capable of treating Parkinson’s by reducing the clusters of aggregated α-synuclein inside cells.
In doing so, the research team behind the study, “A New Glucocerebrosidase Chaperone Reduces α-Synuclein and Glycolipid Levels in iPSC-Derived Dopaminergic Neurons from Patients with Gaucher Disease and Parkinsonism,” published in the Journal of Neuroscience, have likely also found a treatment for Gaucher disease, advancing the understanding of molecular processes causing the two conditions.
The driving force behind the study was Dr. Ellen Sidransky, a senior researcher at the National Human Genome Research Institute (NHGRI), who 15 years ago made the link between the two diseases. She has spent the last 28 years studying Gaucher disease — a time well-spent considering the potential impact of the new findings, made in collaboration with colleagues at the National Institute of Neurological Disorders and Stroke (NINDS) and the National Center for Advancing Translational Sciences (NCATS).
“Until now, drugs used to treat Gaucher disease have not been able to enter the brain and reach those neurons that are affected in the most severe forms of Gaucher disease or in Parkinson’s disease,” said Dr. Sidransky. “It’s really exciting to have found a molecule that theoretically could be widely available to treat people with these diseases.”
Dr. Sidransky underscored that the road between the identification of a molecule and an approved drug is long and slippery, providing no guarantees that a medicine will result from the research.
Gaucher is caused by mutations in the GBA1 gene, which also is the most common genetic cause of Parkinson’s disease. The protein produced by the gene, glucocerebrosidase, is an enzyme responsible for clearing certain fats from cells.
Having two copies of the faulty gene, a situation leading to Gaucher, makes fat accumulate in cells of various organs, and lead to symptoms such as frequent bleeding and bruising, weak bones and, importantly, brain disease. While two copies are needed to get Gaucher, people carrying only one mutated GBA1 gene face a high risk of developing Parkinson’s disease.
Dr. Sidransky’s team started out by producing neurons from so-called induced pluripotent stem cells, derived from the skin of Gaucher patients with and without Parkinson’s symptoms. Neurons derived from patients with Parkinson’s symptoms turned out to have accumulated the protein α-synuclein — a telltale sign of the disease.
While this was indeed valuable information, underscoring the links between the two conditions, the research team continued its study. Using a high-throughput drug screening method, allowing researchers to sieve through thousands of molecules in a short time, the team found a molecule that restored the function of the mutant GBA1 enzyme, allowing it to perform its molecular duty of clearing out excessive cellular fats.
That clearance turned out to also involve α-synuclein. As the neurons from Parkinsonian Gaucher patients were treated with the drug, researchers observed how α-synuclein levels dropped.
“This research constitutes a major advance,” said Daniel Kastner, NHGRI scientific director and director of the institute’s Division of Intramural Research, who was not involved in the study. “It demonstrates how insights from a rare disorder such as Gaucher disease can have direct relevance to the treatment of common disorders like Parkinson’s disease.”
Although genetically determined Parkinson’s disease is exceedingly rare, earlier research has shown that the GBA1 enzyme is also dysfunctional in sporadic disease, increasing the likelihood that a potential drug will benefit most patients.
Researchers will next attempt to evaluate the molecule, testing it to see if it could become a drug candidate for the two diseases.