Heparan sulfate proteoglycans mediate prion-like α-synuclein toxicity in Parkinson's in vivo models

Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by progressive motor decline and the aggregation of alpha-synuclein protein. Growing evidence suggests that alpha-synuclein aggregates may spread from neurons of the digestive tract to the central nervous system in a prion-like manner, yet the mechanisms of alpha-synuclein transmission and neurotoxicity remain poorly understood. Animal models that are amenable to high-throughput investigations are needed to facilitate the discovery of disease mechanisms. Here we describe the first Caenorhabditis elegans models in which feeding with alpha-synuclein preformed fibrils (PFFs) induces dopaminergic neurodegeneration, prion-like seeding of aggregation of human alpha-synuclein expressed in the host, and an associated motor decline. RNAi-mediated knockdown of the C. elegans syndecan sdn-1, or other enzymes involved in heparan sulfate proteoglycan synthesis, protected against PFF-induced alpha-synuclein aggregation, motor dysfunction, and dopamine neuron degeneration. This work offers new models by which to investigate gut-derived alpha-synuclein spreading and propagation of disease.

Automated summary

This study demonstrates the mechanisms of gut-derived alpha-synuclein propagation and neurodegeneration using Caenorhabditis elegans models, and shows that RNAi knockdown can protect against this process.