Researchers at Tel Aviv University (TAU) have discovered a new factor in the pathology of Parkinson's disease, which could in the future serve as a target for developing new treatments against this terrible disease that affects almost 10 million of people in the world.
The researchers explain: “We discovered that a variant of the TMEM16F protein, caused by a genetic mutation, promotes the spread of Parkinson's disease through nerve cells in the brain.”
Stav Cohen doctoral student Adiv Mordechai explains: “A key mechanism of Parkinson's disease is the aggregation in brain cells of the protein α-synuclein (in the form of Lewy bodies), which ultimately kills these cells. For many years, researchers have tried to discover how the pathological version of α-synuclein spreads throughout the brain, affecting one cell after another and gradually destroying entire sections of the brain, because α-synuclein must cross the cell membrane to be able to do this and to propagate. We focused on the TMEM16F protein, a regulator located in the cell membrane, as a possible driver of this deadly process.”
First, the researchers genetically engineered a mouse model lacking the TMEM16F gene and derived neurons from the brains of these mice for an in vitro cellular model. Using a specially designed virus, they caused these neurons to express the defective α-synuclein associated with Parkinson's disease and compared the results with those obtained with normal brain cells containing TMEM16F. They found that when the TMEM16F gene was deleted, the α-synuclein pathology spread to fewer healthy neighboring cells compared to spreading from normal cells. The results were validated in vivo on a live mouse model suffering from Parkinson's disease.
Additionally, in collaboration with the Neurological Institute at Sourasky Medical Center in Tel Aviv, researchers looked for mutations (variants) in the TMEM16F gene that could increase the risk of Parkinson's disease. Dr. Ashkenazi explains: “The incidence of Parkinson's disease among Ashkenazi Jews is known to be relatively high, and the Institute is currently conducting a large genetic study of Ashkenazi Jews who carry genes that increase the risk of contracting Parkinson's disease. disease. With their help, we were able to identify a specific TMEM16F mutation that is common in Ashkenazi Jews in general, and in Ashkenazi Parkinson's patients in particular. It was found that cells carrying the mutation secreted more pathological α-synuclein than cells carrying the normal gene. The researchers explain that the mechanism behind the increase in secretion is linked to the biological function of the TMEM16F protein: the mutation increases the activity of TMEM16F, thus affecting membrane secretion processes.
Stav Cohen Adiv Mordechai adds: “In our study, we discovered a new factor causing Parkinson's disease: the TMEM16F protein, which mediates the secretion of the pathological protein α-synuclein across the cell membrane. towards the cellular environment. Picked up by nearby healthy neurons, the defective α-synuclein forms inside and gradually spreads throughout the brain, damaging more and more brain cells. Our results mark TMEM16F as a possible new target for the development of effective treatments against Parkinson's disease that can stop or reduce the secretion of defective α-synuclein in brain cells. We may thus be able to slow or even stop the spread of the disease through the brain.”
Dr. Ashkenazi emphasizes that the research is still in its early stages and a number of questions remain to be explored: Does inhibiting TMEM16F actually reduce the symptoms of Parkinson's disease? Does the lipid composition of cell membranes play a role in the spread of disease in the brain? Is there a link between TMEM16F mutations and the prevalence of Parkinson's disease in the population?
The search continues.
The study was led by Dr. Avraham Ashkenazi and Stav Cohen doctoral student Adiv Mordechai from the Department of Cellular and Developmental Biology at TAU's Faculty of Medical and Health Sciences and the Sagol School of Neuroscience. Other contributors included: Dr. Orly Goldstein, Prof. Avi Orr-Urtreger, Prof. Tanya Gourevitch and Prof. Nir Giladi from the TAU Faculty of Medical and Health Sciences and Sourasky Medical Center in Tel Aviv , as well as other researchers from TAU and the University of Haifa. The study was supported by the Aufzien Family Center for the Prevention and Treatment of Parkinson's Disease of the TAU. The article was published in the scientific journal Aging Cell.
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