Israeli researchers discover new target for Parkinson’s treatments

Tel Aviv University team’s discovery marks a potential breakthrough towards developing effective treatments for the degenerative neurological condition.

By World Israel News Staff

Researchers at Tel Aviv University (TAU) discovered a new factor in the pathology of Parkinson’s disease, a university spokesperson said Tuesday, which in the future may serve as a target for developing new treatments for this terrible ailment, affecting close to 10 million people worldwide.

“We found that a variant of the TMEM16F protein, caused by a genetic mutation, enhances the spread of Parkinson’s pathology through nerve cells in the brain,” the research team said in a joint statement.

The 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. 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,” explained doctoral student Stav Cohen Adiv Mordechai.

“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.”

During their initial work, the researchers genetically engineered a mouse model without the TMEM16F gene, and derived neurons from the brains of these mice for an in-vitro cellular model.

Using a specially engineered virus, they caused these neurons to express the defective α-synuclein associated with Parkinson’s and compared the results with outcomes from normal brain cells containing TMEM16F.

They found that when the TMEM16F gene had been deleted, the α-synuclein pathology spread to fewer healthy neighboring cells compared to the spread from normal cells.

The results were validated in-vivo in a living mouse model of Parkinson’s 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.

“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,” Dr. Ashkenazi explained.

“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.

“In our study, we discovered a new factor underlying Parkinson’s disease: the protein TMEM16F, which mediates secretion of the pathological α-synuclein protein through the cell membrane to the cell environment,” said  Stav Cohen Adiv Mordechai.

“Picked up by healthy neurons nearby, the defective α-synuclein forms Lewy bodies inside them, and gradually spreads through the brain, damaging more and more brain cells. Our findings mark TMEM16F as a possible new target for the development of effective treatments for Parkinson’s disease.”

“If, by inhibiting TMEM16F, we can stop or reduce the secretion of defective α-synuclein from brain cells, we may be able to slow down or even halt the spread of the disease through the brain.”

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