Yale Scientists May Have Found How Parkinson's Disease Spreads Through the Brain
Researchers at Yale School of Medicine have identified two proteins that help toxic α-synuclein enter healthy neurons, potentially paving the way for treatments that slow or stop Parkinson's progression.
New Clue to Parkinson's Disease Progression
Scientists from Yale School of Medicine (YSM) may have uncovered how Parkinson's disease spreads through the brain. The study, published in Nature Communications, points to two membrane proteins, mGluR4 and NPDC1, as key transporters that carry misfolded α-synuclein into healthy brain cells.
Parkinson's disease is a progressive neurological disorder characterized by the buildup of misfolded α-synuclein. This toxic protein moves from one neuron to another, worsening symptoms over time. Until now, it was unclear how α-synuclein enters healthy cells after escaping dying ones.
Tracking How α-Synuclein Enters Brain Cells
Led by senior author Stephen Strittmatter, MD, PhD, the team produced 4,400 groups of cells, each displaying a different surface protein, and tested whether misfolded α-synuclein would bind to any. The vast majority showed no interaction, but 16 surface proteins did bind. Among them were mGluR4 and NPDC1, both found on dopamine-producing neurons in the substantia nigra, the brain region most affected by Parkinson's.
Further experiments in mice confirmed the role of these proteins. Normal mice exposed to misfolded α-synuclein developed protein accumulations and Parkinson's-like symptoms, while mice lacking functional mGluR4 or NPDC1 did not. In a separate model, removing either gene reduced symptom progression and lowered death risk.
Potential for Future Therapies
Current treatments primarily manage symptoms without significantly slowing the disease. Blocking the spread of α-synuclein between neurons could provide a way to slow or halt progression. With nearly 90,000 new cases annually in the U.S. and an aging population, the need for disease-modifying therapies is growing. Strittmatter emphasizes that understanding this molecular mechanism offers a promising target for future drugs.
