A newly discovered small molecule may offer a way to slow down or stop the progression of Parkinson’s disease, researchers say.
A key feature of Parkinson’s disease, a protein named α-synuclein, accumulates in an abnormal form in brain cells causing them to degenerate and die.
However, it has been difficult to target α-synuclein because it does not have a fixed structure and keeps changing its shape, making it difficult for drugs to target. Because higher levels of the protein in the brain speed the degeneration of brain cells, scientists have looked for ways to decrease the protein production as a form of treatment.
In 2014, M. Maral Mouradian, professor of neurology and director of the Rutgers Robert Wood Johnson Medical School Institute for Neurological Therapeutics, contacted Matthew D. Disney, chemistry professor at Scripps Research in Florida, to explore a new idea for treating Parkinson’s disease using a technology he developed.
Disney’s method matches RNA structure with small molecules or drug-like compounds. The two collaborators believed they could use the technology to find a drug that targets the messenger RNA that codes for α-synuclein, which causes the disease, in order to reduce production of the protein in the brains of Parkinson’s patients.
Since drugs can’t treat the protein itself, they thought RNA could offer a more robust and reliable target.
They were right. The new study in the Proceedings of the National Academy of Sciences shows that targeting messenger RNA allowed the team to find a compound that prevents making the harmful Parkinson’s protein.
This new compound, named Synucleozid, reduces specifically α-synuclein levels and protects cells against the toxicity of the misfolded form of the protein, suggesting that it has the potential to prevent disease progression.
“We found the molecule to be very selective at both the RNA level and the protein level,” Disney says.
Parkinson’s, which affects 1 million people in the United States and over 10 million worldwide according to the Parkinson’s Foundation, is a neurodegenerative disorder with no cure. Symptoms develop slowly over time and can be debilitating to patients, who most recognizably develop tremor, slow movements, and a shuffling gait.
“We want to prevent these protein clumps from forming in the first place before they do damage and lead to advancing disease.”
“Currently, there is no cure for Parkinson’s disease, and it is truly a devastating disease. For the first time, we discovered a drug-like compound that has the potential to slow down the disease before it advances through an entirely new approach,” Mouradian says. The new treatment would be most effective for people in the early stages of the disease with minimal symptoms, she says.
“Several other experimental drugs currently being tested for Parkinson’s disease are antibodies that target a very late stage of α-synuclein protein aggregates. We want to prevent these protein clumps from forming in the first place before they do damage and lead to advancing disease,” she says. “This new compound has the potential to do that and could change the course of life for people with this devastating disease.”
This discovery is highly promising and Mouradian says she’s eager for the next steps in optimizing and testing the compound. Additionally, the method can benefit another devastating disease that also has α-synuclein clumps, known as Dementia with Lewy Bodies.
The new concept of targeting RNA to reduce protein production may also apply to other challenging diseases because of their similar undruggable proteins including Alzheimer’s disease, Mouradian says.
“The reach of our study could go beyond people with Parkinson’s disease to many other neurodegenerative diseases.”
Source: Rutgers University