Exosomal transmission of α-synuclein initiates Parkinson's disease-like pathology

Abstract

The intercellular transmission of -synuclein is proposed to be involved in the pathogenesis of Parkinsons disease (PD)1. Supporting this transmission hypothesis, -synuclein has been identified to act as a prion2 and has been found in cerebrospinal fluid (CSF), blood, and saliva3. However, the mechanism required to initiate the pathogenic spread of -synuclein in the body that results in PD remains unclear. Here we identify a mechanism for the loading of -synuclein into exosomes, resulting in prion-like transmission that is mediated by the ubiquitin ligase activator, Ndfip1. Risk factors associated with PD, including metal toxicity, lysosome dysfunction and pesticide exposure,4 stimulate the upregulation of Ndfip1 and increase the loading of -synuclein into exosomes. We used this pathway to promote the loading of endogenous -synuclein into exosomes, that when intranasally delivered to either wild type or M83 transgenic mice, resulted in Parkinsons-like pathology including motor impairments and brain amyloids. Recipient cells require -synuclein for pathogenesis, as delivery of exosomes containing -synuclein to Snca knockout mice did not generate brain amyloids or Parkinsons-like motor impairments. Our results demonstrate a novel mechanism to initiate the prion-like spread of -synuclein in exosomes, following exposure to risk factors for PD.