UAB study identifies promising target for Parkinson’s disease

UAB study identifies promising target for Parkinson’s disease
A recent UAB study about Parkinson's disease is shedding new light on the complex causes behind the neurologic illness. Parkinson's generally affects people in the older population, with about 60,000 new cases documented annually, though early onset Parksinson's disease affects a small amount of the U.S. population, diagnosed at age 50 or younger. (UAB/Contributed)

An international research team led by scientists at the University of Alabama at Birmingham has identified a potential target for therapeutics that might help slow the progression of Parkinson’s disease.

In findings published in the Journal of Biological Chemistry, the researchers compare different forms of alpha-synuclein, and specifically point to beta-sheet fibrillar forms of the alpha-synuclein protein, as a promising target.

Laura Volpicelli-Daley is making strides in Parkinson’s research. (UAB)

Alpha-synuclein is a protein found in the brain. While its role in a healthy brain is not completely understood, scientists know that, in conditions such as Parkinson’s disease, Lewy body dementia and Alzheimer’s disease, alpha-synuclein clumps into aggregates that damage neurons. The UAB-led research team looked at several forms of alpha-synuclein to determine which is most responsible for brain damage and, thus, the most likely target for therapeutic intervention.

“We’ve long known that the aggregation or clumping of alpha-synuclein plays an important role in diseases such as Parkinson’s,” said Laura Volpicelli-Daley, Ph.D., assistant professor in the Department of Neurology in the School of Medicine. “Our funding agencies — the Michael J. Fox Foundation and support from the UAB Udall Center for Excellence in Parkinson’s Disease Research — have made study of alpha-synuclein a priority. We think that, by preventing alpha-synuclein from forming aggregates, we can prevent progression of the disease.”

Volpicelli-Daley, in concert with biochemist Nunilo Cremades, Ph.D., at the University of Zaragoza, Spain, examined three structural forms of alpha-synuclein in animals. There has been major debate whether alpha-synuclein oligomers — several alpha-synuclein molecules that associate together, or fibrils — with a defined protein structure called amyloid, are most responsible for toxicity in Parkinson’s disease.

“Our findings indicate that the form most toxic to neurons was a structure referred to as beta-sheet fibrillar fragments,” Volpicelli-Daley said. “This is a form of alpha-synuclein that makes overlapping sheets of the protein, which subsequently develop into long filaments. The filaments can then break into smaller fragmented pieces. We hypothesize that the smaller fibrillar fragments are the most toxic to neurons because they are able to attract and corrupt normal alpha-synuclein, causing it to form aggregates that spread throughout the neuron, causing damage to the brain.”

The team suggests that the damage caused by the fragments and subsequent aggregation of normal alpha-synuclein is responsible for a reduction in the chemical messenger dopamine, which is essential for coordinated movement. Loss of dopamine is well-associated with Parkinson’s disease.

The team found that oligomers have some toxic effects on brain cells, but not to the same degree as fibril fragments.

“All this suggests that beta-sheet fibrillar fragments specifically should be a target for development of therapeutic strategies, such as immunotherapy, that might reduce the formation and propagation of this form of alpha-synuclein,” Volpicelli-Daley said. “This strategy may work to slow or stop the progression of Parkinson’s and other disorders that involve alpha-synuclein, such as Lewy body dementia.”

Parkinson’s disease is a neurodegenerative disorder. Symptoms develop slowly over years and include tremor, limb rigidity, slowed movement, and gait and balance issues. There is no cure, but there are treatment options to slow the progression of the disease through medications or surgery.

Approximately 60,000 Americans are diagnosed with Parkinson’s every year, and there are more than 10 million people worldwide with the disease.

Other key contributors in the study were Jessica Froula, who worked in Volpicelli-Daley’s laboratory, and Marta Castellana-Cruz, in both Cremades’ lab at the University of Zaragoza and Christopher Dobson’s lab at the University of Cambridge.

The research study was chosen as an Editor’s Pick, representing the top-rated papers published in the Journal of Biological Chemistry across the field of biological chemistry. These articles are accompanied by additional content summarizing the new findings and featuring the scientists involved.

This story originally appeared on the University of Alabama at Birmingham’s UAB News website.

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