APDA-funded research finds new role for alpha-synuclein

APDA-funded research finds new role for alpha-synuclein

July 30, 2019 – Alpha-synuclein is a protein that is known to clump within the nerve cells of people with Parkinson’s disease (PD) into clusters known as Lewy bodies. Despite extensive research about the protein, many key questions about alpha-synuclein remain insufficiently answered, including: What are the normal roles of alpha-synuclein in the brain? What is the relationship between Lewy body formation and nerve cell death in PD? One of our APDA-funded researchers has uncovered pivotal research that sheds light on these questions.

There has also been conflicting research over whether alpha-synuclein has a role within the nucleus – the membrane-enclosed area within the cell that contains the cell’s DNA or genetic code. In most research about alpha-synuclein, its role at the nerve endings, and not in the nucleus, is studied.

Recently, one of APDA’s George C. Cotzias Fellowship awardees, Vivek Unni, MD, PhD, Associate Professor of Neurology at Oregon Health and Science University in Portland, Oregon, and member of APDA’s Scientific Advisory Board, published a paper which delves into these issues. He discovered that alpha-synuclein does indeed play a vital role in the cell’s nucleus – as a DNA repair protein. In the normal course of a nerve cell’s life, its DNA can become damaged from various environmental insults. Dr. Unni showed that alpha-synuclein is part of the cell’s reaction to this damage, binding to the DNA and helping to repair it. He also demonstrated that with increased clumping of alpha-synuclein into Lewy bodies, less alpha-synuclein is present in the nucleus and more DNA damage is seen.

Taken together, Dr. Unni hypothesized that when an initiating factor triggers the accumulation of alpha-synuclein into Lewy bodies outside the nucleus, the protein is no longer available to do its repair work inside the nucleus. Damage to the DNA builds up and leads to the cell death associated with PD. This is a completely new theory as to how the Lewy body causes problems for the nerve cell – that the accumulations of alpha-synuclein do damage by pulling the alpha-synuclein away from its work in the nucleus.

This new understanding of alpha-synuclein’s function could open up new ways of thinking about treatments for PD. Perhaps a treatment would introduce more alpha-synuclein into the nucleus or help repair DNA in the absence of nuclear alpha-synuclein.

The George C. Cotzias Fellowship is a three-year APDA award granted to a promising young physician scientist to aid in the establishment of his or her career in PD research and patient care. Dr. Unni was granted this Fellowship in 2016 and this year marks his third year of the award. APDA is proud to have played a key role in Dr. Unni’s groundbreaking work.

“Receiving the Cotzias Fellowship from APDA has helped to solidify my career as a physician-scientist, trying to solve the fundamental questions of Parkinson’s disease. The funding has allowed me to test brand new theories about what is happening in the nerve cells of people with PD and may hopefully lead us one step closer to a new treatment for PD,” Dr. Unni said.