Yale Scientists Identify Two Membrane Proteins That Drive Parkinson's Disease Spread Through the Brain
Key Insights
Yale researchers identified mGluR4 (search) and NPDC1 (search) as critical transporters that carry misfolded α-synuclein (search) into healthy neurons, revealing how Parkinson's disease (search) spreads through the brain.
In mouse models, genetically removing either protein prevented toxic protein accumulation, reduced Parkinson's-like symptoms, and lowered the risk of death.
The study, published in Nature Communications, screened 4,400 cell surface proteins and found 16 that bind misfolded α-synuclein (search), with mGluR4 (search) and NPDC1 (search) confirmed as functional transporters.
A research team at Yale School of Medicine has uncovered a molecular mechanism that may explain how Parkinson's disease (search) spreads from neuron to neuron, a discovery that could pave the way for therapies that slow or even halt disease progression rather than merely managing symptoms.
The study, published in Nature Communications, identifies two membrane proteins—mGluR4 (search) and NPDC1 (search)—as critical transporters that carry misfolded α-synuclein (search) into healthy brain cells. Misfolded α-synuclein is widely recognized as "the pathologic hallmark of Parkinson's disease (search)," said senior author Stephen Strittmatter, MD, PhD, Vincent Coates Professor of Neurology and chair of the Department of Neuroscience at YSM.
"If we understood how it gets into neurons, we could perhaps block or slow down the progression of the disease," Strittmatter said. "We need to understand the molecular mechanism of how it spreads."
The Growing Burden of Parkinson's Disease (search)
Parkinson's disease (search) is a progressive neurological disorder in which brain cells gradually become damaged and die. According to the Parkinson's Foundation, approximately 1.1 million Americans are currently living with the disease, and nearly 90,000 new cases are diagnosed each year. The condition commonly causes movement-related symptoms including tremors, impaired balance, and slower movement, which develop as misfolded α-synuclein (search) accumulates in motor neurons. As the toxic protein spreads to additional neurons, the disease continues to worsen.
The need for disease-slowing therapies is expected to become even more pressing in the years ahead. Parkinson's disease (search) and other neurodegenerative disorders primarily affect older adults, and the number of Americans over age 65 is projected to rise substantially over the coming decades, increasing the population at risk.
A Systematic Screen Reveals Key Transporters
To investigate how α-synuclein (search) gains entry into healthy cells, Strittmatter and his team produced 4,400 groups of cells, each engineered to display a different surface protein. They then tested whether misfolded α-synuclein would bind to any of them.
The vast majority showed no interaction. However, 16 surface proteins did bind to the toxic protein. Among these were mGluR4 (search) and NPDC1 (search), two proteins found on dopamine-producing neurons in the substantia nigra—the brain region most heavily affected by Parkinson's disease (search). The team subsequently confirmed that these proteins actively transported misfolded α-synuclein (search) into the cells.
Genetic Knockout Models Confirm Functional Role
The researchers next explored whether these proteins were responsible for helping α-synuclein (search) move from neuron to neuron in living animals. They genetically engineered mice so that either mGluR4 (search) or NPDC1 (search) no longer functioned, then exposed the animals to misfolded α-synuclein.
Normal mice developed accumulations of the toxic protein in their brains and went on to show Parkinson's-like symptoms. In contrast, mice lacking functional mGluR4 (search) or NPDC1 (search) did not. In a separate mouse model of Parkinson's disease (search), removing the genes for either protein also reduced symptom progression and lowered the risk of death.
Together, the findings indicate that mGluR4 (search) and NPDC1 (search) work as partners to transport misfolded α-synuclein (search) into neurons, at least in mice.
A Path Toward Disease-Modifying Therapies
Strittmatter emphasized that this mechanism represents a promising target for future therapies. Existing treatments mainly help manage symptoms and do not significantly slow the underlying disease. Blocking the spread of α-synuclein (search) between neurons could provide a way to slow or even halt Parkinson's progression.
"We have an aging population. How we can stop or slow neurons from dying is an enormous problem," Strittmatter said. "This is really the time to make some inroads into figuring out how to slow it down."