α-Synuclein pre-formed fibrils induce prion-like protein aggregation and neurotoxicity in C. elegans models of Parkinson's disease

Chen, M.; Vincent, J.; Ezeanii, A.; Wakade, S.; Yerigenahally, S.; Mor, D. E.

doi:10.1101/2021.11.11.468276

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bioRxiv · 10.1101/2021.11.11.468276

α-Synuclein pre-formed fibrils induce prion-like protein aggregation and neurotoxicity in C. elegans models of Parkinson's disease

Chen, M.·Vincent, J.·Ezeanii, A.·Wakade, S.·Yerigenahally, S.·Mor, D. E.

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Abstract

Parkinsons disease (PD) is a debilitating neurodegenerative disorder characterized by progressive motor decline and the aggregation of -synuclein protein. Growing evidence suggests that -synuclein aggregates may spread from neurons of the digestive tract to the brain in a prion-like manner. While rodent models have recapitulated gut-to-brain -synuclein transmission, animal models that are amenable to high-throughput investigations are needed to facilitate the discovery of disease mechanisms. Here we describe the first C. elegans models in which feeding with -synuclein pre-formed fibrils (PFFs) induced prion-like dopamine neuron degeneration and seeding of aggregation of human -synuclein expressed in the host. PFF acceleration of -synuclein aggregation in C. elegans muscle cells was associated with a progressive motor deficit, whereas feeding with -synuclein monomer produced much milder effects. RNAi-mediated knockdown of the C. elegans syndecan sdn-1, and enzymes involved in heparan sulfate proteoglycan biosynthesis, afforded protection from PFF-induced seeding of aggregation and toxicity, as well as dopaminergic neurodegeneration. This work offers new models by which to investigate gut-derived -synuclein spreading and propagation of disease.

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Chen, M., Vincent, J., Ezeanii, A., Wakade, S., Yerigenahally, S., Mor, D. E.. 2021-11-13. α-Synuclein pre-formed fibrils induce prion-like protein aggregation and neurotoxicity in C. elegans models of Parkinson's disease. https://doi.org/10.1101/2021.11.11.468276

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