Abstract
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.
Highlights
Parkinson’s disease (PD) is a progressive neurological disorder defined by the loss of nigrostriatal dopaminergic neurons and formation of α-synuclein-positive Lewy bodies
Adult SD rats were intravenously administered with either RVG9R:α-synuclein, RVG9R: green fluorescent protein (GFP), or appropriate RVG9R or cargo controls and, after 24 hours, distinctive axonal human-specific α-synuclein and somatic GFP stainings were detectable in various central nervous system (CNS) regions (Supplementary Fig. 1b)
To assess the biodistribution of RVG9R-mediated cargo delivery, animals were given a single intravenous RVG9R:GFP administration and, after 24 hours, GFP expression was detectable in the CNS only when complexed with RVG9R (Supplementary Fig. 1c)
Summary
Parkinson’s disease (PD) is a progressive neurological disorder defined by the loss of nigrostriatal dopaminergic neurons and formation of α-synuclein-positive Lewy bodies. By interacting with anionic amino acids on the surface of proteins, we hypothesized that RVG9R could be used to enable efficient protein transduction into the CNS following peripheral administration, without it affecting the physiological activities of the cargo protein Using this approach, we demonstrate for the first time that systemic delivery of pathological α-synuclein pffs using this method can lead to selective pathology, neurodegeneration, and functional deficits in the rat CNS and ENS. We demonstrate for the first time that systemic delivery of pathological α-synuclein pffs using this method can lead to selective pathology, neurodegeneration, and functional deficits in the rat CNS and ENS This occurs in a pattern that strikingly mirrors that reported in early-stage, idiopathic PD patients. The strategy we used for transvascular delivery of α-synuclein could be leveraged to deliver other pathogenic and/or therapeutic proteins to the CNS
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