Transmission of misfolded α-synuclein between neurons is a key mechanistic feature of Parkinson’s and in the creation of Lewy pathology. Despite the prion-like nature of Parkinson’s, it is not yet known why some cell populations are resistant to pathology development. We hypothesise that an extracellular neuronal coat, the perineuronal net (PNN), could be a factor underlying neuronal resistance in Parkinson’s. A proteomic screen of extracellular brain lysate with PNN-derived glycans identified the entire synuclein family. Using surface plasmon resonance, the PNN glycans, heparin sulfate & chondroitin sulfate E, bound monomeric & oligomeric alpha-synuclein. The role of the PNN in alpha-synuclein uptake & pathology development was investigated using an in vitro neuronal culture which developed PNNs. In the culture, neuronal uptake of pathogenic alpha-synuclein was reduced by 66% in PNN-enwrapped neurons. Digestion of the PNN removed this resistance and significantly increased the level of alpha-synuclein pathology observed in culture. To determine relevance to the patient condition, the PNN density in affected brain regions from Parkinson’s patients was analysed and compared to non-demented controls. PNN densities were unchanged in Parkinson’s brains and no PNN neurons contained Lewy pathology. These results have established the PNN as a novel binder of α-synuclein and as a barrier against alpha-synuclein uptake & pathology development. This opens a new avenue for the development of therapeutics in Parkinson’s and synucleinopathies as isolating the key component of this interaction could allow rescue of α-synuclein transmission and toxicity via chelation of extracellular misfolded α-synuclein.