Parkinson’s disease may spread throughout the brain with the help of two proteins on the surface of motor neurons, according to a new study from Yale University School of Medicine (YSM). This discovery could open the door to treatments aimed not only at managing symptoms but also slowing or even stopping the progression of the disease.
Parkinson’s disease is a progressive neurological disease in which brain cells gradually become damaged and die. A key feature of the disease is the accumulation of a misfolded protein called alpha-synuclein. This toxic protein moves from one neuron to another, making symptoms worse over time.
Until now, scientists did not fully understand how alpha-synuclein entered healthy neurons after escaping from dying neurons. New research published in nature communications point to two membrane proteins, mGluR4 and NPDC1, as important transporters that help carry misfolded proteins into healthy brain cells.
New clues about Parkinson’s disease progression
Lead author Steven Strittmatter, MD, Vincent Coates Professor of Neurology and Director of Neuroscience at YSM, said the findings could lead to more effective ways to combat Parkinson’s disease.
Misfolded alpha-synuclein is a “pathological hallmark of Parkinson’s disease,” he says.
“If we can understand how it enters neurons, perhaps we can block or slow the progression of the disease,” he added. However, to do so, “we need to understand the molecular mechanisms of how infection spreads.”
Tracking how alpha-synuclein enters brain cells
Neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease are an increasingly important public health challenge in the United States. According to the Parkinson’s Disease Foundation, approximately 1.1 million Americans live with Parkinson’s disease, and nearly 90,000 new cases are diagnosed each year.
The disease usually causes movement-related symptoms such as tremors, impaired balance, and slowness of movement. These problems occur when misfolded α-synuclein accumulates in motor neurons. The disease continues to progress as the protein spreads to additional neurons.
The researchers suspected that alpha-synuclein might be able to enter healthy cells by binding to proteins on the cell surface. For the study, Strittmatter and his team created 4,400 cell groups, each engineered to display a different surface protein. They then tested whether misfolded alpha-synuclein bound to any of them.
The majority showed no interaction. However, 16 surface proteins bound to the toxic protein. These included mGluR4 and NPDC1, two proteins found in dopaminergic neurons in the substantia nigra, the brain region most affected by Parkinson’s disease. The research team discovered that these proteins transport misfolded alpha-synuclein into cells.
Stop the spread of Parkinson’s disease
The researchers next investigated whether these proteins play a role in helping alpha-synuclein move from neuron to neuron. They genetically engineered mice so that either mGluR4 or NPDC1 was nonfunctional and exposed the animals to misfolded alpha-synuclein.
Normal mice developed toxic protein buildup in their brains and developed Parkinson’s disease-like symptoms. In contrast, mice lacking functional mGluR4 or NPDC1 did not. In another mouse model of Parkinson’s disease, removing the genes for either protein also reduced the progression of symptoms and the risk of death.
Taken together, these findings indicate that, at least in mice, mGluR4 and NPDC1 function as partners to transport misfolded α-synuclein into neurons.
Strittmatter says this mechanism is a promising target for future treatments. Existing treatments primarily help manage symptoms and cannot significantly slow the progression of the underlying disease. Blocking the spread of alpha-synuclein between neurons could provide a way to slow or even stop the progression of Parkinson’s disease.
Growing need for better Parkinson’s disease treatment
The need for treatments that slow disease progression is expected to further increase in the coming years. Parkinson’s disease and other neurodegenerative diseases primarily affect older adults, and the number of Americans age 65 and older is expected to increase significantly in the coming decades, increasing the population at risk.
“The population is aging, and the big question is how can we prevent or slow the death of neurons,” Strittmatter says. “Now is the time to look for ways to slow it down.”
