Balance and movement improved in animal model of Parkinson’s disease


Mark Wheeler 


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.

Scientists discover protective strategy against pesticide-linked Parkinson’s disease

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.

Story Source:

The above post is reproduced from materials provided by University of California – Los Angeles Health SciencesNote: Materials may be edited for content and length.

Journal Reference:

  1. 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 EmbryosEnvironmental Health Perspectives, 2016; DOI: 10.1289/EHP141
CLR01 shows its therapeutic effect again! This time for improving neuronal survival after spinal cord injury.

CLR01 shows its therapeutic effect again! This time for improving neuronal survival after spinal cord injury.

Spinal cord injury (SCI) in humans typically has a poor prognosis, including permanent losses in mobility and sensation, reflecting in part our very limited capacity for neural regeneration.

To understand these limits on recovery after SCI, MBL Associate Scientist Jennifer Morgan studies the lamprey, a fish that can spontaneously regenerate neurons after SCI and regain mobility remarkably well.

Morgan’s team recently discovered that one risk factor for neural death after SCI is the accumulation of a protein, synuclein, in the damaged neurons. Together with their collaborators, Morgan’s team also identified a drug, CLR01, that reduces the accumulation of synuclein in lamprey neurons after SCI, and thereby improves their survival. They published their study this week in Experimental Neurology.

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CLR01 Presentation Wins Prize at Alpha-Synuclein Meeting

CLR01 Presentation Wins Prize at Alpha-Synuclein Meeting

Dr. Franziska Richter, PhD, DVM, a former member of Marie-Françoise Chesselet‘s laboratory at UCLA, won an Abstract Prize at the Alpha-Synuclein: Gateway to Parkinsonism- Innsbruck Course for her presentation, entitled The molecular tweezer CLR01 reduces alpha-synuclein accumulation and improves motor deficits in a mouse model of Parkinson’s disease. The Prize was given by the Directors of the meeting and F1000. While at UCLA, Dr. Richter, who currently works at the Institute of Pharmacology, Pharmacy and Toxicology at the University of Leipzig , led the study of CLR01 in a mouse model of Parkinson’s disease and found improvement in motor deficits in correlation with reduction of brain pathology. The study gives hope that CLR01 can be developed as therapy for Parkinson’s disease and other synucleinopathies.


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Dr. Richter (left) with Pam Bower, Secretary of the MSA Coalition (center) and Dr. Nadia Stefanova, University of Innsbruck (right).