Parkinson's disease (PD) is an α-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 α-synuclein preformed fibrils (pff). We show that a single systemic administration of α-synuclein pff triggers pathological transformation of endogenous α-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 α-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 α-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.

Centre for Reconstructive Neuroscience Institute of Experimental Medicine 142 20 Prague 4 Czech Republic

Department of Basic and Clinical Neuroscience Institute of Psychiatry Psychology and Neuroscience King's College London London SE5 9RX UK

Department of Biochemistry University of Cambridge Cambridge CB2 1GA UK

Department of Neuroimaging Kings College London London SE5 8AF UK

Department of Neurology Addenbrooke's Hospital Cambridge CB2 0QQ UK

John van Geest Centre for Brain Repair Department of Clinical Neuroscience University of Cambridge Cambridge CB2 0PY UK

MRC Centre for Neurodevelopmental Disorders King's College London London SE1 1UL UK

School of Biomedical Sciences Faculty of Biological Sciences University of Leeds Leeds LS2 9JT UK

Wellcome Trust MRC Cambridge Stem Cell Centre Cambridge CB2 1QR UK

Wolfson Brain Imaging Centre Department of Clinical Neurosciences University of Cambridge Cambridge CB2 0QQ UK

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