Systemic α-synuclein injection triggers selective neuronal pathology as seen in patients with Parkinson's disease

Parkinson's disease (PD) is an alpha-synucleinopathy characterized by the progressive loss of specific neuronal populations. Here, we develop a novel approach to transvascularly deliver proteins of complex quaternary structures, including alpha-synuclein preformed fibrils (pff). We show that a single systemic administration of alpha-synuclein pff triggers pathological transformation of endogenous alpha-synuclein in non-transgenic rats, which leads to neurodegeneration in discrete brain regions. Specifically, pff-exposed animals displayed a progressive deterioration in gastrointestinal and olfactory functions, which corresponded with the presence of cellular pathology in the central and enteric nervous systems. The alpha-synuclein pathology generated was both time dependent and region specific. Interestingly, the most significant neuropathological changes were observed in those brain regions affected in the early stages of PD. Our data therefore demonstrate for the first time that a single, transvascular administration of alpha-synuclein pff can lead to selective regional neuropathology resembling the premotor stage of idiopathic PD. Furthermore, this novel delivery approach could also be used to deliver a range of other pathogenic, as well as therapeutic, protein cargos transvascularly to the brain.

Automated summary

A novel approach was developed to deliver complex quaternary structure proteins transvascularly to rats, leading to neuropathological changes resembling the premotor stage of Parkinson's disease. This new delivery method could potentially be used for pathogenic and therapeutic protein cargos to the brain.