Researchers at Yale School of Medicine believe they have identified how the toxic protein behind Parkinson’s disease moves between brain cells, alongside a potential way to halt that spread before it causes further damage. Published in the journal Nature Communications, the findings point to two specific proteins acting as entry points that allow the disease to progress, offering a new avenue for treatments that could target the condition itself rather than just its symptoms.
Parkinson’s disease affects roughly 1.1 million people in the United States, according to the Parkinson’s Foundation, with nearly 90,000 new diagnoses recorded each year. The progressive neurological disorder gradually impairs movement, balance and coordination, typically producing symptoms such as tremors, slowed movement, stiffness and difficulty with balance. At the heart of the disease is a misfolded protein called alpha-synuclein, which builds up inside brain cells and is believed to spread from neuron to neuron as the condition worsens. Despite this being a well-established feature of Parkinson’s, scientists had not previously understood exactly how the protein manages to enter healthy neurons in the first place.
Screening thousands of proteins to find the answer
To investigate, the Yale research team screened thousands of proteins found on the surface of cells in search of a mechanism that could explain alpha-synuclein’s spread. That search led them to two proteins, named mGluR4 and NPDC1, which appear to function together as a receptor complex. According to the researchers, this pairing plays a central role in allowing misfolded alpha-synuclein to bind to and enter otherwise healthy nerve cells, effectively acting as a doorway for the disease to progress from one neuron to the next.
Blocking the receptor protected brain cells in mice
To test their theory, the team exposed mice to alpha-synuclein fibrils, clumps of the protein known to trigger Parkinson’s-like damage in the brain. Animals that lacked both mGluR4 and NPDC1 showed dopamine-producing neurons that were largely protected from degeneration, in stark contrast to normal mice exposed to the same fibrils. The researchers found that both proteins were required for the toxic protein to be efficiently taken up by cells, and that blocking either one on its own was enough to significantly cut the amount of alpha-synuclein entering healthy neurons.
Further laboratory work using human neurons derived from stem cells reinforced these findings. When researchers prevented alpha-synuclein from binding to the mGluR4–NPDC1 receptor complex, the spread of the toxic protein between cells was similarly reduced, suggesting the mechanism identified in mice also holds in human cell models.
A potential target for future treatments
The results suggest that interrupting alpha-synuclein’s ability to enter healthy neurons could break the cycle that allows Parkinson’s to spread through the nervous system over time. The research team believes future drugs or antibodies designed to target the mGluR4–NPDC1 receptor complex could offer a way to slow the disease’s progression by blocking this spread directly.
Senior author Professor Stephen Strittmatter said the goal of the research had been to identify a treatment capable of modifying the disease itself, rather than one that simply manages its symptoms, describing the receptor complex as a promising target for future disease-modifying therapies.
Still early days for any new treatment
The researchers were careful to stress that the work remains at a preclinical stage. Any treatment developed from the discovery would need to undergo further laboratory research and human clinical trials before it could become available to patients. Even so, experts have said the findings offer valuable new insight into one of the central unanswered questions in Parkinson’s research: precisely how misfolded alpha-synuclein travels from one neuron to another as the disease advances.
