Yale scientists may have found how Parkinson’s disease spreads through the brain

Parkinson’s disease is a progressive neurological disorder in which brain cells gradually become damaged and die. A key feature of the disease is the buildup of a misfolded protein called α-synuclein. As this toxic protein moves from one neuron to another, it contributes to the worsening of symptoms over time.

Until now, scientists have not fully understood how α-synuclein enters healthy neurons after escaping from dying ones. A new study published in Nature Communications points to two membrane proteins, mGluR4 and NPDC1, as critical transporters that help carry the misfolded protein into healthy brain cells.

A New Clue to Parkinson’s Disease Progression

Senior author Stephen Strittmatter, MD, PhD, Vincent Coates Professor of Neurology and chair of the Department of Neuroscience at YSM, says the findings could lead to more effective ways to combat Parkinson’s disease.

Misfolded α-synuclein is “the pathologic hallmark of Parkinson’s disease,” he says.

“If we understood how it gets into neurons, we could perhaps block or slow down the progression of the disease,” he adds. But to do that, “we need to understand the molecular mechanism of how it spreads.”

Tracking How α-Synuclein Enters Brain Cells

Neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease are becoming an increasingly significant public health challenge in the United States. According to the Parkinson’s Foundation, about 1.1 million Americans are living with Parkinson’s disease, and nearly 90,000 new cases are diagnosed each year.

The disease commonly causes movement related symptoms including tremors, impaired balance, and slower movement. These problems develop as misfolded α-synuclein accumulates in motor neurons. As the protein spreads to additional neurons, the disease continues to progress.

Researchers suspected that α-synuclein might gain entry into healthy cells by attaching to proteins on the cell surface. To investigate, 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 them were mGluR4 and NPDC1, two proteins found on dopamine producing neurons in the substantia nigra, the brain region most heavily affected by Parkinson’s disease. The team discovered that these proteins transported misfolded α-synuclein into the cells.

Blocking the Spread of Parkinson’s Disease

The researchers next explored whether these proteins were responsible for helping α-synuclein move from neuron to neuron. They genetically engineered mice so that either mGluR4 or NPDC1 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 or NPDC1 did not. In a separate mouse model of Parkinson’s disease, removing the genes for either protein also reduced symptom progression and lowered the risk of death.

Together, the findings indicate that mGluR4 and NPDC1 work as partners to transport misfolded α-synuclein into neurons, at least in mice.

Strittmatter says 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 between neurons could provide a way to slow or even halt Parkinson’s progression.

Growing Need for Better Parkinson’s Treatments

The need for disease slowing therapies is expected to become even greater in the years ahead. Parkinson’s disease 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.

“We have an aging population. How we can stop or slow neurons from dying is an enormous problem,” says Strittmatter. “This is really the time to make some inroads into figuring out how to slow it down.”