Yale scientists have identified two proteins on the surface of brain cells that allow Parkinson's disease to spread from neuron to neuron, a finding that could lead to the first treatments capable of slowing the disease rather than just managing its symptoms.
The discovery, published in Nature Communications, homes in on a question that has nagged at Parkinson's researchers for years. A misfolded protein called alpha-synuclein accumulates inside brain cells and is widely accepted as the pathologic hallmark of the disease. As this toxic protein moves from one neuron to the next, symptoms worsen: tremors intensify, movement slows, and balance deteriorates. Roughly 1.1 million Americans live with Parkinson's, and nearly 90,000 new cases are diagnosed each year [1].
What has remained unclear is exactly how alpha-synuclein escapes dying cells and enters healthy ones. A team led by Dr. Stephen Strittmatter, chair of neuroscience at Yale School of Medicine, set out to fill that gap. The researchers produced 4,400 groups of cells, each engineered to display a different surface protein, then tested whether misfolded alpha-synuclein would bind to any of them. Sixteen proteins showed some interaction, but two stood out: mGluR4 and NPDC1. Both are found on dopamine-producing neurons in the substantia nigra, the brain region hit hardest by Parkinson's.
The team then genetically engineered mice so that either protein no longer functioned, and exposed the animals to misfolded alpha-synuclein. Normal mice developed the expected protein accumulations and Parkinson's-like symptoms. Mice lacking functional mGluR4 or NPDC1 did not. In a separate Parkinson's model, removing either gene also reduced symptom progression.
The results indicate that the two proteins work as a receptor complex, ferrying the toxic protein across cell membranes. Strittmatter noted that drugs targeting mGluR4 are a realistic prospect, since some mGluR4 compounds have already entered clinical trials for other conditions.
Current Parkinson's treatments address symptoms but do not significantly slow the underlying neurodegeneration. If the findings translate to humans, blocking alpha-synuclein's entry into healthy neurons could interrupt the cycle of cell-to-cell spread and give physicians a tool to alter the course of the disease itself.