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 firstCaenorhabditis elegansmodels 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 theC. eleganssyndecansdn-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.

Parkinson’s disease (PD) is a multifactorial disorder involving both motor and non-motor symptoms caused by the progressive death of distinct neuronal populations, including dopaminergic neurons in the substantia nigra. The deposition of aggregated α-synuclein protein into Lewy body inclusions is a hallmark of the disorder, and α-synuclein pathology has been found in the enteric nervous system (ENS) of PD patients up to two decades prior to diagnosis. In combination with the high occurrence of gastrointestinal dysfunction in early stages of PD, current evidence strongly suggests that some forms of PD may originate in the gut. In this review, we discuss human studies that support ENS Lewy pathology as a characteristic feature of PD, and present evidence from humans and animal model systems that α-synuclein aggregation may follow a prion-like spreading cascade from enteric neurons, through the vagal nerve, and into the brain. Given the accessibility of the human gut to pharmacologic and dietary interventions, therapeutic strategies aimed at reducing pathological α-synuclein in the gastrointestinal tract hold significant promise for PD treatment.

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 brain in a prion-like manner. While rodent models have recapitulated gut-to-brain α-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 α-synuclein pre-formed fibrils (PFFs) induced prion-like dopamine neuron degeneration and seeding of aggregation of human α-synuclein expressed in the host. PFF acceleration of α-synuclein aggregation in C. elegans muscle cells was associated with a progressive motor deficit, whereas feeding with α-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 α-synuclein spreading and propagation of disease.