Novel animal model defines genetic contributions for neuron-to-neuron transfer of α-synuclein

Cell-to-cell spreading of misfolded alpha-synuclein (alpha-syn) is suggested to contribute to the progression of neuropathology in Parkinson's disease (PD). Compelling evidence supports the hypothesis that misfolded alpha-syn transmits from neuron-to-neuron and seeds aggregation of the protein in the recipient cells. Furthermore, alpha-syn frequently appears to propagate in the brains of PD patients following a stereotypic pattern consistent with progressive spreading along anatomical pathways. We have generated a C. elegans model that mirrors this progression and allows us to monitor alpha-syn neuron-toneuron transmission in a live animal over its lifespan. We found that modulation of autophagy or exo/endocytosis, affects alpha-syn transfer. Furthermore, we demonstrate that silencing C. elegans orthologs of PD-related genes also increases the accumulation of alpha-syn. This novel worm model is ideal for screening molecules and genes to identify those that modulate prion-like spreading of alpha-syn in order to target novel strategies for disease modification in PD and other synucleinopathies.