University of Utah researchers identify molecule that could treat, stall Parkinson's disease

Daniel Scoles, associate professor of neurology, and Stefan Pulst, chair of neurology, discuss a newly identified molecule that could help treat Parkinson's and slow its progression.

Daniel Scoles, associate professor of neurology, and Stefan Pulst, chair of neurology, discuss a newly identified molecule that could help treat Parkinson's and slow its progression. (University of Utah Health)



Estimated read time: 3-4 minutes

SALT LAKE CITY — Scientists at 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 about the discovery in the Journal of Biological Chemistry, detailing how the molecule slows down cells' 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, slender fibers called fibrils, which is thought to lead to the death of dopamine-producing neurons and can result in neurodegenerative disorders like Parkinson's disease, Lewy body dementia or multiple system atrophy.

Dopamine is a neurotransmitter, meaning that it serves as a messenger between nerve cells and is involved in moving the body, learning, memory, sleeping and waking and even mood regulation. When 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 the symptoms worsen as the disease progresses and more neurons die.

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

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

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

Duong Huynh, a research associate professor in the University of Utah's department of neurology, used gene-editing tools to insert a gene from fireflies that encodes a light-producing protein into human genes. When the protein turned on, it made the human cells glow whenever the alpha-synuclein gene was active and dim when it's less active.

Scoles and Huynh worked with Stefan Pulst, the chairman of the department of neurology at the university, and researchers at the National Center for Advancing 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 in the center's facility.

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

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

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

The team is planning on conducting further research to see whether the molecule can be developed into a potential treatment for Parkinson's and the other neurodegenerative disorders that involve alpha-synucelein protein aggregates. They will also look at other molecules they found during their tests that may inhibit alpha-synuclein production.

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