Researchers at UCLA have developed a molecular compound that improves balance and coordination in mice with early stage Parkinson’s disease. Further, the drug, called CLR01, reduced the amount of a toxic protein in the brain that is thought to be one of the prime culprits in the development of the disorder.
Parkinson’s disease is a nervous system disorder that affects movement. It’s estimated that as many as 1 million Americans live with Parkinson’s, and that roughly 60,000 are diagnosed with it each year. There is no cure. The disease is chronic and progressive, and over time can worsen from tremors in a person’s hands and slow movements, to impaired balance and coordination and, ultimately, overall rigidity of the body, including difficulty swallowing and speaking.
While the cause is not known, growing evidence points to the protein alpha-synuclein. The protein binds together in “clumps,” called aggregates, becoming toxic and killing brain neurons that produce dopamine, a neurotransmitter needed to send signals among neurons involved in controlling movements.
Earlier research by Gal Bitan, an associate professor of neurology at the David Geffen School of Medicine at UCLA, and colleagues led to the development of CLR01, which is known as a molecular tweezer — a complex compound capable of disrupting the formation of toxic protein clumps. Shaped like the letter “C,” CLR01 wraps around chains of lysine, a basic amino acid that is a constituent of most proteins. In the previous work in zebrafish, the scientists showed that the tweezer could decrease the clumping of alpha-synuclein and prevent its negative effects without detectable toxicity or side effects to normal, functioning cells in the brain.
In this study in mice, the UCLA researchers took a more refined approach. It turns out there are two toxic forms of alpha-synuclein. One is the proteins that clump together, forming aggregates. The second is a soluble form that is difficult to detect because it is not very stable. This is the more toxic form and is thought to be the culprit affecting the neurons. In the new study, the researchers used a treatment of CLR01 that did not affect the aggregated form of alpha-synuclein; instead, it only reduced the soluble form. This proved to be sufficient to help improve movements in mice. These findings are important because they suggest that researchers may not need to focus on the aggregates if the toxic soluble form of alpha-synuclein can be reduced or destroyed.
CLR01 previously showed a strong therapeutic effect in a zebrafish model of Parkinson’s. This study is the first to demonstrate CLR01’s effectiveness in a mammal, one of the last important steps before human clinical trials.
The researchers are now working on optimizing the blood-brain barrier penetration of CLR01 and measuring all the pharmacological features necessary for applying to the Food and Drug Administration to begin the first human, clinical trials.
Bitan and Dr. Marie-Françoise Chesselet, the Charles H. Markham professor of neurology at UCLA, are the senior authors of the study. Franziska Richter, assistant professor at the University of Leipzig in Germany, is the first author.
The paper was published in the online edition of the journal Neurotherapeutics.
This work was supported by multiple funding agencies, including the National Institutes of Health, RJG Foundation, the Michael J. Fox Foundation, Team Parkinson/Parkinson Alliance, the American Parkinson’s Disease Association, and gifts to the Center for the Study of Parkinson’s Disease at UCLA.
Exposure to a group of common pesticides, called dithiocarbamates, has long been associated with an increased risk of Parkinson’s disease, although the mechanism by which the compounds exert their toxicity on the brain has not been completely understood. A new UCLA study sheds light on the toxicity of the compounds while also suggesting a strategy that may help protect against the disease.
The research focused on the fungicide ziram, which is used extensively in heavily agricultural areas such as California’s Central Valley and which causes the loss of the main source of dopamine in the central nervous system. Loss of this source, called dopaminergic neurons, is associated with Parkinson’s disease.
The pesticide-linked damage starts with ziram’s ability to increase concentrations of a protein, called α-synuclein, which is abundant in the human brain. The α-synuclein proteins then aggregate, or clump together, harming neighboring neurons. This phenomenon also occurs in Parkinson’s disease that is not due to pesticide exposures, making it a target for researchers searching for a broad treatment.
In the new study, conducted in zebrafish, researchers found that elimination of the α-synuclein protein protected the zebrafish against the ziram-induced loss of dopamine neurons. Because most cases of Parkinson’s disease appear to be at least partially caused by environmental factors such as pesticide exposure, these findings support the approach that targeting α-synuclein could slow or stop the progression of Parkinson’s in most people with the disease, said study lead author Jeff Bronstein, a professor of neurology and director of movement disorders at the David Geffen School of Medicine at UCLA.
“These findings add to the growing literature linking pesticide exposure and the development of Parkinson’s disease and offers important insights into the mechanisms of ziram toxicity,” Bronstein said. “A better understanding of the pathogenesis of Parkinson’s disease will ultimately lead to new treatments and eventually a cure.”
The study was published June 15 in the peer-reviewed journal Environmental Health Perspectives.
First, the researchers developed a model of Parkinson’s in zebrafish — the first such animal model of the disease — and exposed them to ziram so that they lost dopamine. They found that the fish exposed to the ziram did not swim properly, evidence of a Parkinson’s-like condition.
Then the researchers genetically knocked out the α-synuclein protein in the zebrafish and exposed them to ziram again. The ziram failed to make the fish sick, and the animals continued to swim properly.
Next, the researchers gave the non-protected zebrafish an investigational drug, CLR01, being developed by UCLA scientist Gal Bitan who co-authored the study, which breaks up the protein aggregates, or clumps, in Parkinson’s patients. They found that the drug provided protection from the Parkinson’s-like condition in the fish.
“Getting rid of the protein genetically or breaking up the aggregates with this drug protected against ziram toxicity,” Bronstein said. “This is important — it establishes that environmental toxins work on same pathway that is in play in those genetically disposed to Parkinson’s. Most important, we can use drugs being developed now on patients who get Parkinson’s because of ziram exposure.”
Going forward, Bronstein and his team will determine if other environmental substances are using the same mechanism to cause Parkinson’s. They will also conduct further research on CLR01 in preparation for clinical trials in human subjects.
About 70 percent of Parkinson’s cases cannot be explained by genetics, Bronstein said, so the new finding could be vital to a large percentage of patients whose disease is not genetically caused.
The above post is reproduced from materials provided by University of California – Los Angeles Health Sciences. Note: Materials may be edited for content and length.
- Jeff M. Bronstein, Alvaro Sagasti, Thomas Schrader, Frank-Gerrit Klärner, Chase Yamashiro, Mark C. Stahl, Kelley O’Donnell, Binh Nguyen, Magdalena I. Ivanova, Gal Bitan, Lisa Barnhill, Aaron Lulla. Neurotoxicity of the Parkinson’s Disease-Associated Pesticide Ziram Is Synuclein-Dependent in Zebrafish Embryos. Environmental Health Perspectives, 2016; DOI: 10.1289/EHP141
On January 21st, 2016, we will hold the first meeting of the BTDD project in Europe. The meeting will have two parts – the first is a Mini Workshop hosted by the CRC 1093 at the University of Duisburg-Essen (see agenda below). This Mini Workshop is open to all scientists and the general public. The second part is a closed meeting for participating scientists only. We are grateful to CRC 1093 for their hospitality and look forward to a stimulating and vibrant meeting.
On October 25th, 2015, the Parkinson Alliance held “Outside the Box” – a private event to raise funds for supporting the drug development research efforts in Gal Bitan‘s laboratory. Dr. Bitan was introduced by Dr. Jeff Bronstein, Director of the Movement Disorders Clinic at UCLA and BTDD collaborator. The event was a great success and the money raised exceeded the expectations of the organizers.
We are very grateful to Carol Walton and the Parkinson Alliance, to the inspirational John Ball of Team Parkinson who has had Parkinson’s disease for more than half of his life yet keeps running marathons to raise money for the cause, to Susie and Al Lewin who hosted the even in their gorgeous Altadena home, to Edna Ball who spent many hours helping to organize the event, to Kim Vu from Vicarious Catering for the delicious food, to Jennifer Smith and her Fighting for Our Brains campaign, who came up with creative ideas to help raise funds for this event, and last but not least, to Melissa Charsette Bitan who provided wonderful entertainment with her band – Scott (Bugs) Allen on bass and horns, Trevor Jennings on keyboard, and Keith Williams on drums.