Molecular Mediation of Prion-like α-Synuclein Fibrillation from Toxic PFFs to Nontoxic Species

Braak's theory described Parkinson's disease (PD) progression as prion-like α-synuclein (αSyn) spreading, which fundamentally subverts the understanding of pathogenesis. The pathological αSyn spreading pathway includes uptake, propagation, and release. However, the previous disease models were limitedly focusing on amyloid propagation/aggregation, which significantly impedes the mechanism exploration in spreading pathways and related therapeutic development. The spreading model can be achieved using recombinant αSyn preformed fibrils (PFFs), which seeds endogenous αSyn monomer to aggregation and causes substantial pathology and neurotoxicity. Here, we determined that dihydromyricetin (DHM), a natural flavonoid extracted from Ampelopsis grossedentata, can promote the fibrillization of prion-like PFF and induce propagation to form a distinct strain. Furthermore, administration of DHM significantly reduced prion-like PFF-induced propagation and neurotoxicity. The discovery of inducing infectious and neurotoxic PFF to a nontoxic strain resulting in neuron protection via promoting the fibrillization of PFF rather than inhibiting advances the understanding of the prion-like spreading mechanism and helps in developing treatments against PD and related α-synucleinopathies.