Researchers Identify Proteins that Spread Parkinson’s Pathology in the Brain

Two proteins found on the surface of motor neurons in the brain may be essential in the progression of Parkinson’s disease, according to new Yale School of Medicine (YSM) research.

Parkinson’s disease is a neurodegenerative condition where neurons in the brain slowly break down and die. Cell death is caused by the accumulation of a misfolded protein called α-synuclein, which spreads from neuron to neuron.

The mechanism by which α-synuclein spreads among cells, however, remains unknown. Now, a new study published in Nature Communications suggests that two membrane proteins—mGluR4 and NPDC1—are major players in transporting misfolded α-synuclein into healthy neurons after it escapes from dying neurons.

The finding could help develop more effective treatments for Parkinson’s disease, says senior author Stephen Strittmatter, MD, PhD, Vincent Coates Professor of Neurology and chair of the Department of Neuroscience at YSM.

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.”

Neurodegenerative diseases like Alzheimer’s and Parkinson’s are a growing health concern in the United States. The Parkinson’s Foundation currently estimates that around 1.1 million Americans are diagnosed with Parkinson’s disease, and nearly 90,000 more people join their ranks every year.

People with Parkinson’s disease often experience motor issues, such as tremors, trouble with balance, and slowed movement. These symptoms are caused by the accumulation of misfolded α-synuclein in motor cells in the brain. As α-synuclein spreads between neurons, symptoms worsen.

One way α-synuclein could enter new cells is by binding to surface proteins. To determine whether this was the case, Strittmatter and his colleagues created 4,400 batches of cells, each expressing different cell surface proteins, and observed whether they bound to misfolded α-synuclein.

Most cell surface proteins did not. But 16 did, including two found in the human dopamine neurons of the substantia nigra, a region of the brain that degenerates in Parkinson’s disease. The researchers found that these two, called mGluR4 and NPDC1, transported misfolded α-synuclein into the cell.

These results suggested to Strittmatter and his colleagues that the two cell surface proteins could be involved in moving α-synuclein from neuron to neuron. To test this, the researchers genetically modified mice to have non-functional copies of either mGluR4 or NPDC1 and then introduced misfolded α-synuclein.

In regular mice, misfolded α-synuclein accumulated in their brains once introduced, and the mice developed Parkinson’s-like symptoms. But mice without working mGluR4 or NPDC1 didn’t. The researchers also found that knocking out the genes for these two cell surface proteins in a mouse model of Parkinson's disease helped reduce the risk of death and progression of symptoms.

Altogether, the researchers’ experiments suggest that mGluR4 and NPDC1 work together to move misfolded α-synuclein into neurons in mice.

The findings offer a potential avenue for treating Parkinson’s disease, Strittmatter says. Current Parkinson’s disease interventions focus on reducing symptoms but do not effectively prevent progression of the disease. Going directly after the spread of α-synuclein could provide treatments to slow or halt the course of Parkinson’s disease, he says.

New, effective treatments will be especially important in the coming decades. Parkinson’s and other neurodegenerative diseases largely impact older people. The number of Americans over the age of 65 is expected to increase over the next few decades—meaning that more people will be at risk of developing Parkinson’s disease.

“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.”