University of Utah researchers identify molecule that could treat and delay Parkinson’s disease

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

Daniel Scoles, 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 thought to help nerve cells communicate. However, in unhealthy brains, this protein aggregates – or clumps together – inside neurons to create small, thin fibers called fibrils, which are said to cause the death of dopamine-producing neurons and can lead to neurodegenerative disorders like Parkinson’s disease, 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, so symptoms worsen as the disease progresses and more neurons die.

Current treatments for Parkinson’s disease are drugs that work in a similar way to dopamine and can help send these messages between nerve cells to control symptoms, but there is currently no cure for the disease or any way to help it. ‘stop its progress.

While the death of neurons in Parkinson’s disease is still a mystery, researchers have looked at alpha-synuclein as the culprit, so being able to slow the production of the potentially toxic protein could help slow the death of these. neurons and thus slow down neuronal degeneration.

“Most cases of Parkinson’s disease are characterized by an overabundance of alpha-synuclein,” said Scoles. “The dominant idea is that if you reduce its overall abundance, that would be therapeutic.”

Duong Huynh, an associate research 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 turned on, it made human cells glow whenever the alpha-synuclein gene was active and dimmed when it was less active.

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

The team used a robotic setup to assess 155,885 different compounds at the center’s facilities.

They determined that a molecule called A-443654 could possibly inhibit production of the protein. Huynh died in 2018, and a postdoctoral researcher named Mandi Gandelman performed further testing and found that the molecule slows down the alpha-synuclein gene in human cells and also reduces production of the alpha-protein gene. synuclein.

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

“We can stop production, but we also have to degrade what’s already aggregated,” Gandelman said. “The more it is aggregated, the more toxic it becomes.”

The team plans to conduct further research to see if the molecule can be developed into a potential treatment for Parkinson’s disease and other neurodegenerative disorders that involve aggregates of alpha-synucelein proteins. They will also look at other molecules found during their tests that may inhibit alpha-synuclein production.

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