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 online 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.
Alpha-synuclein is a protein found in the human brain. While its role in a healthy brain is not completely understood, science does 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 different structural forms of alpha-synuclein to determine which was most responsible for damage to the brain, 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. 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."
Laura Volpicelli-Daley, Ph.D., assistant professor in the Department of Neurology in the School of Medicine
Volpicelli-Daley, in concert with biochemist Nunilo Cremades, Ph.D., at the University of Zaragoza, Spain, examined three structural forms of alpha-synuclein in animal models. There has been major debate in the field 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 also showed that oligomers had some toxic effects on brain cells, but not to the same degree as the 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."
University of Alabama at Birmingham
Volpicelli-Daley, L. et al. (2019) Defining α-synuclein species responsible for Parkinson disease phenotypes in mice. Journal of Biological Chemistry. doi.org/10.1074/jbc.RA119.007743.