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Researchers at the University of Utah identify a molecule that could treat and stop Parkinson's disease

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SALT LAKE CITY – Scientists at the University of Utah Health made a discovery that could lead to a new way to treat Parkinson's disease and potentially stop its progression.

Daniel Scoles, an associate professor of neurology at the university, and his team of researchers recently published a report on the discovery in the Journal of Biological Chemistry, detailing how the molecule slows down cellular production of a protein called alpha-synuclein.

In a healthy brain, alpha-synuclein is believed to help nerve cells communicate. However, in diseased brains, this protein aggregates, or clumps together, within neurons to create small, thin fibers called fibrils, which are believed to cause dopamine-producing neurons to die and can lead to neurodegenerative disorders such as disease. Parkinson's, Lewy body. dementia or multisystem atrophy.

Dopamine is a neurotransmitter, which means that it serves as a messenger between nerve cells and is involved in body movement, learning, memory, sleep and wakefulness, and even mood regulation. When the neurons that produce dopamine die, people can develop Parkinson's disease, a disorder of the central nervous system that affects movement and balance, sometimes causing tremors. It affects more than 10 million people worldwide and is degenerative, with symptoms worsening as the disease progresses and more neurons die.

Current treatments for Parkinson's are drugs that act similar to dopamine and can help send these messages between nerve cells to control symptoms, but there is no current cure for the disease or any way to stop its progression.

Although the death of neurons in Parkinson's is still a mystery, researchers have been looking for -synuclein as the culprit, so being able to slow down the production of the potentially toxic protein could help slow down the death of those neurons and thus therefore, slow down neural degeneration.

"Most cases of Parkinson's disease are characterized by an overabundance of alpha-synuclein," Scoles said. "The prevailing thinking is that if you reduce its overall abundance, this would be therapeutic."

Duong Huynh, a research associate professor in the department of neurology at the University of Utah, used gene editing tools to insert a firefly gene that encodes a light-producing protein into human genes. When the protein was activated, it caused human cells to glow when the alpha-synuclein gene was active and dim when it was less active.

Scoles and Huynh worked with Stefan Pulst, chairman of the university's neurology department and researchers at the National Center for the Advancement of Translation Sciences to use these light-producing cells to run millions of assessments to see how a variety of small molecules would affect the alpha-synuclein gene.

The team used a robotic setup to evaluate 155,885 different compounds at the center's facility.

They determined that a molecule called A-443654 could likely inhibit the production of the protein. Huynh died in 2018, and a postdoctoral researcher named Mandi Gandelman conducted further tests and found that the molecule slowed down the alpha-synuclein gene in human cells and also reduced production of the alpha-synuclein protein gene.

The molecule can also relieve the stress that alpha-synucellin aggregates place on cells that can cause them to die. Gandelman explained that this decrease in stress on the cell may allow cells to break down aggregates that have already formed.

"We can stop production, but we also need to degrade what is already added," says Gandelman. . "The more aggregated it is, the more toxic it becomes."

The team plans to conduct further research to see if the molecule can become a potential treatment for Parkinson's and other neurodegenerative disorders involving alpha-aggregated protein sinucelein. They will also look at other molecules that they found during their tests that can inhibit alpha-synuclein production.

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