Journal
LIFE SCIENCE ALLIANCE
Volume 5, Issue 11, Pages -Publisher
LIFE SCIENCE ALLIANCE LLC
DOI: 10.26508/lsa.202201366
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- Medical College of Georgia at Augusta University
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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.
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.
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