Emerging Mechanistic Insights in Parkinson's Disease: The Role of Neuronal Surface Proteins

Yale researchers have identified neuronal surface proteins mGluR4 and NPDC1 as potential facilitators of Parkinson disease propagation, presenting new targets and biomarkers for intervention.

The prevailing model holds that misfolded α-synuclein spreads between neurons and drives clinical progression, but how it engages cell surfaces to transmit remained unclear.

The Yale team reports that mGluR4 and NPDC1 may facilitate neuron-to-neuron transport of misfolded α-synuclein in preclinical models. Using cellular trafficking assays and animal studies, they showed protein-dependent uptake and transfer and observed increased α-synuclein spread when these proteins were present—supporting a role as conduits for transfer in the models tested.

At the membrane level, misfolded α-synuclein appears to bind or be internalized via neuronal surface receptors or cofactors, which then mediate trans-synaptic or vesicular transfer to neighboring neurons. Linking the identified proteins to binding, endocytosis, and vesicle-mediated export clarifies a discrete cell-surface step in the propagation cascade.