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

UCLA RESEARCH ALERT

Mark Wheeler 

FINDINGS

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.

BACKGROUND

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.

METHOD

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.

IMPACT

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.

AUTHORS

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.

JOURNAL

The paper was published in the online edition of the journal Neurotherapeutics.

FUNDING

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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European Project Meeting in January 2016

European Project Meeting in January 2016

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.

CRC1093 Workshop 21st of January 2016

Parkinson Alliance Supports Our Research

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.

 

Targeting HIV in Semen to Shut Down AIDS

Targeting HIV in Semen to Shut Down AIDS

A new paper from the groups of Jan Münch and James Shorter in the prestigious journal eLife reveals that CLR01 can not only break semen-related amyloid and reduce HIV infection, but also that CLR01 destroys membrane of the virus itself and therefore can act as a highly effective microbicide against AIDS and other viral diseases, including herpes and hepatitis C.

Read the Press Release

Can CLR01 help against cancer?

Can CLR01 help against cancer?

We don’t usually think of cancer as a disease related to amyloid or to protein aggregation. In cancer, the control systems that dictate the cell life cycle are lost and cells begin to proliferate out of control. A key element in the control system is the “tumor suppressor” protein, p53.  p53 has been described as “the guardian of the genome” because it protects genes from mutation. However, the gene encoding p53 can be mutated itself, leading to formation of a dysfunctional protein, loss of control, and cancer.

An interesting recent discovery is that a sub-group of the mutations lead to protein aggregation, similar to what happens in amyloidoses, such as Alzheimer’s or Parkinson’s diseases. This finding is highly important because p53 acts as a homotetramer (a protein complex made of four identical subunits) and to be functional, each one of the four subunits has to have the correct structure. If just one is mutated, the complex falls apart. Because our genome has two copies of each gene, if a structure-altering mutation occurs in one of the copies and that mutation leads to a dysfunctional protein, 50% of the protein produced will be dysfunctional. But when four intact copies are needed for the protein to function and one copy of the gene is mutated, only 1/16, or 6.25%, of the tetramers will be normal and functional.

The problem with amyloid formation is that the normal protein tends to co-aggregate with the bad one, reducing the percentage of available normal protein even more. And if that is not bad enough, protein “cousins” of p53, called p63 and p73, also co-aggregate with the mutant protein, reducing the cells ability to control its processes even more. Moreover, the aggregates can be transmitted to other cells and induce abnormal aggregation in them, a possible mechanism for the propagation of cancer.

In addition to the loss of control, the rogue protein aggregates themselves are cytotoxic, similarly to protein aggregates in other amyloidoses. This is where the molecular tweezer, CLR01, might help. CLR01 is known to alter the formation of the toxic aggregates and facilitate their degradation by the body’s clearance mechanisms. Can it do that with mutant p53? Facilitate clearance of the mutant protein and possibly release the good protein? To begin to answer these questions, the team of Dr. Danny Segal at Tel Aviv University examined the effect of CLR01 on two prevalent mutant forms of p53 in a series of biophysical and biochemical tests. They found that CLR01 stabilized intermediate-size aggregates of the mutant proteins. Thus, the transition from small oligomers to the intermediate-size aggregates was accelerated, but further aggregation was inhibited when the mutant proteins interacted with CLR01.

These observations led to an important question: are the intermediate aggregates still toxic to cells? When the researchers added the aggregates of mutant p53 itself, without CLR01, to cultured cells, the cells died, but when they added the mixture of mutant p53 with CLR01, the molecular tweezer protected the cells and they survived. These findings suggest that CLR01 may be helpful in cases of cancer caused by p53 mutations because it may help prevent both the formation of toxic protein aggregates and the co-aggregation of healthy protein with the mutated form.

The study was published in the American Chemical Society journal Biochemistry.

CLR01 may hold promise for type-2 diabetes

CLR01 may hold promise for type-2 diabetes

Diabetes is known as a disease of uncontrolled blood-sugar levels because the body does not produce enough insulin, or the insulin that is produced is not used effectively by the body. Most people are not aware that type-2 diabetes is also the most prevalent amyloidosis. In type-2 diabetes, a small protein called Islet Amyloid PolyPeptide (IAPP) forms toxic aggregates that kill the insulin-producing beta cells in the pancreas.
A new study now shows that the molecular tweezer, CLR01, prevents the aggregation of IAPP and its toxicity towards pancreatic cells. The study, which is published in the American Chemical Society (ACS) journal ACS Chemical Biology, shows how CLR01 binds to IAPP, changes its structure, and prevents its aggregation. The study also shows that the blood levels of CLR01 needed for therapeutic effect can be achieved without causing safety concerns.
The new study was led by Gal Bitan‘s group at UCLA in collaboration with Thomas Schrader and Frank Klärner, University of Duisburg-Essen, Elsa Sanches-Garcia, Max-Planck-Institut für Kohlenforschung in Mülheim, and Chunyu Wang, Rensselaer Polytechnic Institute.