A new study published in the Nature Communications journal suggests a link between the spread of the toxic, misfolded protein, a-synuclein, and proteins found on dopamine-producing neurons in the substantia nigra, mGluR4 and NPDC1. Due to a-synuclein being a hallmark of Parkinson’s disease, this newfound connection may enable future treatments that shift away from managing symptoms and instead on slowing or even halting spread.
Parkinson’s disease is a progressive neurological disorder where brain cells become increasingly damaged and die over time as a result of a buildup of the misfolded protein, a-synuclein, resulting in a myriad of symptoms such as tremors, impaired balance, and slower movements that worsen as the toxic protein accumulates in healthy, motor neurons. It is becoming an increasingly notable public health concern in the United States, with about 1.1 million Americans currently living with the disease and nearly 90,000 new cases being diagnosed each year, according to the Parkinson’s Foundation. In fact, the number of Americans over the age of 65 is expected to expand over the coming decades—increasing the pool of individuals at increased risk of developing the disease.
Despite scientists not fully understanding how the abnormal a-synuclein spreads from dying neurons to healthy ones, Stephen Strittmatter, MD, PhD, AB, Vincent Coates Professor of Neurology and Professor of Neuroscience at Yale University, sought to uncover the mystery. He and his team of researchers suspected that the a-synuclein protein may be spread to healthy neurons by attaching to proteins on the cell surface, prompting them to conduct the formal study. In the procedure, the team produced 4,400 groups of cells that were individually engineered to each display a different surface protein to determine whether the a-synuclein would bind to any of them. Interestingly enough, while the majority showed no interaction, 16 surface proteins did in fact bind to the a-synuclein — notably among them being mGluR4 and NPDC1 found in the substantia nigra, the most heavily affected part of the brain by the disease.
Following these successful binding attempts, the team genetically engineered mice to remove functionality from either the mGluR4 or NPDC1 before exposing them to the misfolded protein. While normal mice suffered from abnormal a-synuclein accumulations and displayed Parkinson’s-like symptoms, the ones lacking working mGluR4 or NPDC1 proteins did not — reducing symptoms of progression and lowering the risk of death. As a result of the test, Strittmatter determined that the two proteins work together to transport the toxic a-synuclein that otherwise resulted in worsening symptoms.
When reflecting on the potential implications of the study on Parkinson’s treatments moving forward and the increased demand for such treatment, Strittmatter remarks that “we have an aging population. How we can stop or slow neurons from dying is an enormous problem…This is really the time to make some inroads into figuring out how to slow it down.”
