TY - JOUR T1 - Heparan sulfate proteoglycans mediate prion-like α-synuclein toxicity in Parkinson’s in vivo models JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202201366 VL - 5 IS - 11 SP - e202201366 AU - Merry Chen AU - Julie Vincent AU - Alexis Ezeanii AU - Saurabh Wakade AU - Shobha Yerigenahally AU - Danielle E Mor Y1 - 2022/11/01 UR - https://www.life-science-alliance.org/content/5/11/e202201366.abstract N2 - Parkinson’s disease (PD) is a debilitating neurodegenerative disorder characterized by progressive motor decline and the aggregation of α-synuclein protein. Growing evidence suggests that α-synuclein aggregates may spread from neurons of the digestive tract to the central nervous system in a prion-like manner, yet the mechanisms of α-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 α-synuclein preformed fibrils (PFFs) induces dopaminergic neurodegeneration, prion-like seeding of aggregation of human α-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 α-synuclein aggregation, motor dysfunction, and dopamine neuron degeneration. This work offers new models by which to investigate gut-derived α-synuclein spreading and propagation of disease. ER -