Tel Aviv University (TAU) researchers have made a significant stride in understanding Parkinson’s disease. By identifying a genetic mutation in the TMEM16F protein that fuels the disease’s progression, they’ve opened doors to potential new treatments. This discovery could bring hope to the millions worldwide living with this debilitating condition.
TMEM16F, also known as anoctamin-6 or Ano6, is a protein involved in various cellular functions. It can rapidly translocate phospholipids between the inner and outer leaflets of the plasma membrane in response to calcium signals. This process, known as phospholipid scrambling, plays a crucial role in several biological processes.
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TMEM16F can also function as a calcium-activated non-selective cation channel, allowing the passage of small ions like calcium, sodium, and potassium across the cell membrane.
The TAU study was led by Dr. Avraham Ashkenazi and PhD student Stav Cohen Adiv Mordechai from the Department of Cell 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 Gurevich and Prof. Nir Giladi from TAU’s Faculty of Medical and Health Sciences and the Tel Aviv Sourasky Medical Center, as well as other researchers from TAU and the University of Haifa. The study was backed by the Aufzien Family Center for the Prevention and Treatment of Parkinson’s Disease at TAU. The paper was published in the scientific journal Aging Cell.
“A key mechanism of Parkinson’s disease is the aggregation in brain cells of the protein α-synuclein (in the form of Lewy bodies), eventually killing these cells,” explains Stav Cohen. “For many years researchers have tried to discover how the pathological version of α-synuclein spreads through the brain, affecting one cell after another, and gradually destroying whole sections of the brain. Since α-synuclein needs to cross the cell membrane in order to spread, we focused on the protein TMEM16F, a regulator situated in the cell membrane, as a possible driver of this lethal process.”
By genetically engineering mice without the TMEM16F gene, researchers have uncovered a crucial role for this protein in the progression of Parkinson’s disease. In both in vitro and in vivo models, the absence of TMEM16F significantly hindered the spread of toxic α-synuclein, suggesting that targeting this protein could offer a novel therapeutic strategy for the disease.
In addition, in collaboration with the Neurological Institute at the Tel Aviv Sourasky Medical Center, the researchers looked for mutations (variants) in the TMEM16F gene that might increase the risk for Parkinson’s disease. Dr. Ashkenazi explains: “The incidence of Parkinson’s among Ashkenazi Jews is known to be relatively high, and the Institute conducts a vast ongoing genetic study on Ashkenazi Jews who carry genes increasing the risk for the disease. With their help, we were able to identify a specific TMEM16F mutation which is common in Ashkenazi Jews in general, and in Ashkenazi Parkinson’s patients in particular.” Cells carrying the mutation were found to secrete more pathological α-synuclein compared to cells with the normal gene.
The researchers explain that the mechanism behind increased secretion has to do with the biological function of the TMEM16F protein: the mutation increases the activity of TMEM16F, thereby affecting membrane secretion processes.
