Researchers at Yale School of Medicine say they have identified two proteins on the surface of neurons that help shuttle misfolded alpha-synuclein—a key protein implicated in Parkinson’s disease—into healthy cells, a finding that could point to new strategies aimed at slowing progression.
A study from Yale School of Medicine examined how misfolded alpha-synuclein, a protein that accumulates in Parkinson’s disease, can move from one neuron to another and potentially contribute to worsening symptoms over time.
To investigate how the toxic protein gains entry into healthy neurons, the researchers created 4,400 groups of engineered cells, each displaying a different surface protein, and tested whether misfolded alpha-synuclein would bind to them. The team reported that 16 surface proteins bound to the misfolded protein, and highlighted two—mGluR4 and NPDC1—that appeared to work together to transport the misfolded protein into cells.
In mouse experiments described by the researchers, animals genetically engineered so that either mGluR4 or NPDC1 no longer functioned showed far less accumulation of misfolded alpha-synuclein after exposure and did not develop Parkinson’s-like symptoms seen in normal mice. The team also reported that, in a separate mouse model of Parkinson’s disease, removing the genes for either protein reduced symptom progression and lowered the risk of death.
The findings were reported in Nature Communications and were led by Stephen Strittmatter, a Yale neurologist and neuroscientist, who said understanding how alpha-synuclein gets into neurons could help researchers design approaches to block or slow the disease process.
Parkinson’s treatments today largely focus on managing symptoms and do not reliably slow the underlying disease, according to the researchers. In the United States, the Parkinson’s Foundation estimates that about 1.1 million people are living with Parkinson’s disease and around 90,000 new cases are diagnosed each year.
Strittmatter also pointed to demographic trends—an increasing share of older adults in the population—as adding urgency to efforts aimed at developing therapies that could slow neurodegeneration.
