One more step to victory over Parkinsonism
Scientists have reversed the development of Parkinson's disease in an animal model of the disease
LifeSciencesToday based on ScienceDaily: Parkinson's disease stopped in animal model
Parkinson's disease, a progressive disease of the nervous system, affects millions of people, and it is expected that in the coming decades, due to the worldwide aging of the population, the number of its victims will increase dramatically. Certain treatments can reduce the symptoms of Parkinson's disease, but none of them slows down its development. Although the exact cause of the development of Parkinson's disease is still unknown, scientists recognize the protein α-synuclein as one of its culprits. This protein, naturally present in healthy neurons, common to all patients with Parkinson's disease, turns into a trigger of the disease when the formation of its aggregates begins. Α-synuclein aggregates are toxic and lead to the death of neurons.
In an article published online in the journal Neurotherapeutics (A Novel “Molecular Tweezer” Inhibitor of α-Synuclein Neurotoxicity in Vitro and in Vivo), Professor of neurology at the University of California at Los Angeles (University of California - Los Angeles) Jeff Bronstein and associate professor of Neurology Gal Bitan, together with their colleagues, report on the development of a new compound, "molecular tweezers", which in an animal model blocks the formation of α-synuclein aggregates, suppresses their toxicity and, moreover, reverses the development of already formed aggregates. At the same time, the molecular tweezers do not disrupt the normal functioning of the brain.
Currently, scientists know more than 30 incurable diseases caused by protein aggregation and, as a result, their toxic effects on the brain and other organs, including Parkinson's disease, Alzheimer's disease and type 2 diabetes. Therefore, according to Professor Bronstein, it is extremely important to find a way to stop the aggregation process. Over the past two decades, scientists and pharmaceutical companies have been trying to develop drugs that can prevent abnormal aggregation of proteins, but positive results have not yet been achieved.
The target of drugs for the treatment of Parkinson's disease are α-synuclein aggregates. It is very difficult to find a remedy that affects only these abnormal structures, but it is necessary, since the normal function of non-aggregated α-synuclein naturally located in brain cells should not be disrupted.
According to Professor Bronstein, the normal function of α-synuclein is not completely understood, but it may play a role in interneuronal communication. "The whole difficulty lies in preventing the formation of protein aggregates of α-synuclein and suppressing their toxicity without disrupting its normal function and, of course, the functions of other healthy parts of the brain."
This study is the result of Professor Bronstein's collaboration with Gal Bytan, who developed a molecular tweezer called CLR01. Molecular tweezers are complex compounds capable of binding to other proteins. Shaped like the letter "C", they wrap around chains of the amino acid lysine, which is part of most proteins.
Working first with cell cultures, scientists have found that CLR01 is able to prevent the formation of α-synuclein aggregates, suppress their toxicity and even destroy existing aggregates.
"The most surprising aspect of our work," says Professor Bronstein, "is that, despite the ability of this compound to bind to many proteins, it does not show toxicity and does not have side effects on normal, functioning brain cells."
"We call this unique mechanism 'process-specific' rather than protein-specific inhibition," adds Dr. Baitan, meaning that the target of this compound is only α-synuclein aggregates and nothing else.
After testing CLR01 on cell cultures, the scientists moved on to experiments on tropical freshwater fish, often kept in aquariums. Zebra fish, or danios, are popular laboratory animals because they are easy to genetically modify. They are developing rapidly and have another remarkable property for scientists – almost complete transparency, which facilitates the study of many biological processes.
Embryos of transgenic danios with a Parkinson's disease model expressing human wild-type α-synuclein in neurons were characterized by severe malformations, and most of them died within 48-72 hours as a result of apoptosis of neurons. The addition of CLR01 to water significantly improved the phenotype of animals and their survival, suppressed the aggregation of α-synuclein and reduced the indicators of apoptosis caused by it. It has been found that the expression of α-synuclein suppresses the ubiquitin-proteosomal system of neurons, leading to further aggregation of α-synuclein. Treatment of CLR01 almost completely eliminated the inhibition of proteosomes.
The ability to prevent the formation of α-synuclein aggregates, suppress their toxicity and destroy existing aggregates is a very encouraging result, but, to date, "we have stopped Parkinson's disease only in danio," Professor Bronstein comments on the experimental results. "One way or another, but all these effects of CLR01 are not accompanied by any signs of toxicity. And all this taken together opens up great prospects for the use of CLR01 as a new drug that can slow down or even stop the progression of Parkinson's disease and related diseases. This brings us one step closer to their complete cure."
Scientists are already studying CLR01 in a mouse model of Parkinson's disease and hope that this study will allow us to move on to clinical trials of the compound.
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06.03.2012