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

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Peer-reviewed

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Article

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Authors

He, Xiaoling 
Wood, Tobias C 
Yang, Sujeong 

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.

Description

Keywords

Animals, Brain, Enteric Nervous System, Humans, Neurons, Parkinson Disease, alpha-Synuclein

Journal Title

Mol Psychiatry

Conference Name

Journal ISSN

1359-4184
1476-5578

Volume Title

26

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved
Sponsorship
Medical Research Council (MR/S005528/1)
Alzheimer's Research UK (ARUK-RF2016A-1)
European Commission (242003)
Medical Research Council (MR/R015724/1)
Medical Research Council (MC_PC_12009)
Medical Research Council (MR/K02308X/1)
Wellcome Trust (203151/Z/16/Z)
Medical Research Council (MR/M009041/1)
Biotechnology and Biological Sciences Research Council (BB/N022181/1)
BBSRC (BB/T015403/1)
This study was funded by the Rosetrees Trust (CM234), as well as a fellowship awarded to W.L.K. by the Medical Research Council (MR/S005528/1). R.A.B. receives support from the National Institute for Health Research award as a senior investigator, through the Biomedical Research Center at the University of Cambridge (146281), as well as support from the Wellcome/MRC Cambridge Stem Cell Institute (203151/Z/16/Z). J.C.F.K. is supported by Wings for Life Foundation. S.J.Y. is supported by Alzheimer’s Research UK (ARUK-RF2016A-1). A.C.V. acknowledges funding support from the Medical Research Council (MR/N025377/1 and Centre grant MR/N026063/1). This project has also received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no 242003. The authors would like to thank Prof. M.G. Spillantini, Dr. J. Xia, and Dr. J.N. Skepper for their help in the analysis of the experiments.