People with Parkinson’s disease may spend years struggling with debilitating symptoms, including loss of balance and coordination, inability to move, and difficulty speaking and swallowing. Available treatments only address the symptoms of the disease, not the underlying cause – and because patients can live with the disease for a long time, the effectiveness of current treatments wanes over time. New treatments are needed that can help stave off debilitating symptoms and help patients retain their independence longer.
Now, researchers in the Drug Discovery Lab at UCLA Health have identified a new class of drugs for Parkinson’s based on studies using human cells and in mice. The compound works by reducing the transmission of damaging proteins from affected brain cells to their neighbors. The findings, published in the journal Molecular Brain, introduce a possible new approach to treating Parkinson’s disease.
Cells need to communicate with each other, and they do this by sending out little packets of molecules called exosomes (from exo-, meaning “outside,” and soma, “body”). Many cell types, including brain cells, use exosomes to send messages to other cells, such as “help, I’m under attack!” or “hey, come and collect the garbage.”
In Parkinson’s, aggregates of an improperly folded protein called alpha-synuclein build up in brain cells and cause damage. When a cell gets overwhelmed with the aggregates, it makes more exosomes to help offload the toxic proteins. The disease then spreads to neighboring cells when they take up those exosomes.
“Rather than communicating biochemical messages that help the system, exosomes start to deliver these aggregates,” says associate project scientist Tina Bilousova, one of the lead authors of the study. “The problem is that the aggregates can act as a template to start misfolding of the alpha synuclein in the next cell.”
The consequence of this is that cells with normal alpha-synuclein protein become diseased when the aggregate invades and kickstarts the conversion of the healthy protein to the aggregation-prone form.
Finding a candidate
To prevent the spread of these dangerous proteins throughout the brain, the team searched for compounds that could reduce the production of exosomes. Because exosomes do transmit important and necessary signals, however, the ideal drug would slow down exosome production but not completely stop it.
Earlier published studies described an enzyme known as nSMase2 (neutral sphingomyelinase 2) that helps create exosomes. Brain cells in people with Parkinson’s often have too much of this enzyme, so the team sought to find a drug that would reduce excess nSMase2 activity and bring it back to the normal range.
The team searched the existing literature for molecules known to inhibit nSMase2, and came across cambinol. When they tested it in brain cells grown in the lab, they found it reduced production of exosomes.
This finding made cambinol a good candidate for studying the question of whether limiting exosomes would slow the transmission of toxic aggregates.
In an earlier paper, the researchers showed that cambinol reduced the transmission of a different protein called tau, which is associated with Alzheimer’s disease. That success led them to test the compound in mice engineered to make human alpha-synuclein. These mice displayed many of the signs of Parkinson’s, including loss of motor function, sleep disruptions, and other nervous system effects.
The result: Mice treated with cambinol accumulated less alpha-synuclein in their brains, and their motor function did not deteriorate as fast as the untreated mice.
Further research
Before advancing a compound into human trials, the team will need to make sure the candidate can pass through the protective layer of cells inside the brain’s blood vessels, called the “blood-brain barrier,” and enter brain cells.
“Cambinol may not necessarily be the best compound to take forward in further studies,” says Patricia Spilman, senior scientist at the Drug Discovery Lab at UCLA.
“This is really a proof-of-concept study,” says Varghese John, professor of neurology and director of the Drug Discovery Lab. “Now we go back to the drawing board and will continue to screen for more potent compounds to find a molecule we can develop further.”
The UCLA Molecular Screening Shared Resource (MSSR), led by professor Robert Damoiseaux, has a library of 200,000 different compounds that can be used for this screening, increasing the opportunity to find a more effective compound. Once a compound is found that has the optimum characteristics, including potency, solubility, and the ability to get into the brain, the team will conduct long-term studies in animals to make sure it is safe and effective. After that, it would likely go on to advanced testing before possible human clinical trials as a drug candidate for Parkinson’s. The team has received a PD Seed Grant for this effort from the DGSOM, funded by the Steven and Laurie Gordon Family Foundation.
Even if reduction of nSMase2 activity and the cell-to-cell transmission of alpha-synuclein leads to decreased Parkinson’s symptoms in people, it isn’t likely to be a miracle cure all on its own – but it could become a component of a combination treatment.
“This type of drug might be effective even if it modestly inhibits the production of exosomes and the spread of the toxic protein,” said Spilman. “We could see it working in combination with some of our other approaches to treating neurodegenerative diseases.”
Learn more about the neurology Drug Discovery Lab at UCLA.
Caroline Seydel is the author of this article.
