Researchers from the Hebrew University and Univ Penn State Revealed for the first time the structures of the central protein in the early stages of Parkinson's disease. Dr. Eitan Lerner: "The findings may help in the development of drugs that will help slow down the rate of the disease and possibly even prevent it"
Parkinson's disease is the second most common degenerative disease of the nervous system, after Alzheimer's disease, and it affects more than 10 million people worldwide. The disease begins its development in the nerve cells in the brain stem and is characterized by a gradual impairment of the body's ability to move, such as tremors, muscle stiffness and balance disorders. The damaged neurons in Parkinson's patients are characterized by the appearance of microscopic aggregates called Lewy bodies, which can lead to damage to the function of the nerve cell. These bodies contain incredibly ordered and stable fibers composed of the protein alpha-synuclein, whose function in the brain of a healthy person is to support the transfer of dopamine sacs along the ends of nerve cells. When this protein is not interacting with other intracellular components, it lacks an ordered and defined three-dimensional structure. In fact, such a free protein is able to fold into various unstable structures, which undergo very fast structural changes (microseconds and even faster than that). The alpha-synuclein protein is biologically active when it is folded into a specific structure, but while in some situations its structure will contribute to normal physiological activity, in other situations its structure will support pathology-promoting activity.
In a groundbreaking new study published in the journal Structure by researchers from the Hebrew University and Penn State University in the USA, the mechanism that allows the alpha-synuclein protein to change structures between those that support its normal physiological activity and those that initiate disturbances in the body's activity and lead to Parkinson's disease was discovered. As part of this study, the researchers combined advanced biophysical methods and characterized the various structures of free alpha-synuclein.
Molecules acting in the repair or degenerative pathway
After analyzing the data, Dr. Eitan Lerner's team from the Silverman Institute for Life Sciences at the Hebrew University showed, through the use of advanced spectroscopic methods, that surprisingly parts of these structures maintain a stable structure for times of tens to hundreds of milliseconds. Dr. Lerner explains: "This is a slow enough time that allows local structures within alpha-synuclein to support the various functions of the protein, whether in the normal activity path or the degenerative path."
Using these structures of the free alpha-synuclein protein, and the fact that some of them actually constitute the stages that precede a known activity, whether physiologically normal, or that promotes pathology, it will be possible to develop small molecules that will bind specifically to the structure of the protein in its state that promotes degeneration, and inhibit the formation of its fibers, or alternatively such to bind specifically to the protein structure in its state that encourages normal activity, and stabilize this structure. According to Ms. Sophia Zaer, a student in Dr. Eitan Lerner's laboratory, "it is a protein that may lead to the opposite of what was expected, and our main goal now is to learn how to direct its activity in the normal physiological direction."
According to Dr. Lerner, "This study is a window to a new approach to developing drugs for Parkinson's disease. Our ambition is to continue the biochemical research of the early stages of Parkinson's disease, to try to develop drugs that will improve the neurophysiological function, and slow down or stop the development of the disease."
The research was conducted in collaboration with Ms. Paz Drori, Ms. Joanna Zamel, Mr. Khalil Juron and Dr. Nir Klisman from the Hebrew University of Jerusalem, and was supported by the US National Institutes of Health (NIH), the Passan Foundation, the Israel Institute of Science and the Milner Foundation.
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