|Jeff Bronstein, M.D. '88|
|Gal Bitan, Ph.D.|
But UCLA neurological scientists Jeff Bronstein, M.D. '88, Ph.D., and Gal Bitan, Ph.D., along with their colleagues, report the development of a novel compound known as a "molecular tweezer," which in a living-animal model blocked a-synuclein clumps from forming, stopped the aggregates' toxicity and, further, reversed aggregates that had already formed in the brain. And the tweezers accomplished this without interfering with normal brain function.
The research was published in the journal Neurotherapeutics. Over the last two decades, researchers and pharmaceutical companies have attempted to develop drugs that would prevent abnormal protein aggregation in a variety of diseases, including Parkinson's, but so far, they have had little or no success. While these aggregates are a natural target for a drug, finding a therapy that targets only the aggregates is a complicated process, Dr. Bronstein says. In Parkinson's, for example, a-synuclein is naturally ubiquitous throughout the brain.
Dr. Bronstein collaborated with Dr. Bitan, who had been working with a particular molecular tweezer he had developed called CLR01. Molecular tweezers are complex compounds that are capable of binding to other proteins. Shaped like the letter "C," these compounds wrap around chains of lysine, a basic amino acid that is a constituent of most proteins.
"The most surprising aspect of the work," Dr. Bronstein says of experiments in a cell culture, "is that despite the ability of CLR01 to bind to many proteins, it did not show toxicity or side effects to normal, functioning brain cells." It proved to be "process-specific," meaning the compound attacked only the targeted aggregates and nothing else.
|CLR01 prevents toxic a-synuclein aggregation. The top image shows zebrafish neurons (red) with clumps of human a-synuclein (green). The bottom image shows neurons in zebrafish treated with CLR01. Note the clumps are gone.|
The researchers next tried their tweezers in a living animal, the zebrafish, a tropical freshwater fish commonly found in aquariums. Using a transgenic zebrafish model for Parkinson's disease, the researchers added CLR01 and tracked its effect on the aggregations. They found that, just as in cell cultures, CLR01 prevented a-synuclein aggregation and neuronal death, thus stopping the progression of the disorder in the living-animal model.
The results have been very encouraging, but still, at the end of the day, "we've only stopped Parkinson's in zebrafish," Dr. Bronstein says.
"Nonetheless," he says, "all of these benefits of CLR01 were found without any evidence of toxicity. And taken together, CLR01 holds great promise as a new drug that can slow or stop the progression of Parkinson's and related disorders. This takes us one step closer to a cure."
The researchers are already studying CLR01 in a mouse model of Parkinson's and say they hope this will lead to human clinical trials.