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

Wei-Li Kuan*, Katherine Stott, Xiaoling He, Tobias C. Wood, Sujeong Yang, Jessica C.F. Kwok, Katie Hall, Yanyan Zhao, Ole Tietz, Franklin I. Aigbirhio, Anthony C. Vernon, Roger A. Barker

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)556-567
Number of pages12
JournalMolecular Psychiatry
Volume26
Issue number2
DOIs
Publication statusPublished - 1 Feb 2021
Externally publishedYes

Bibliographical note

Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Fingerprint Dive into the research topics of 'Systemic α-synuclein injection triggers selective neuronal pathology as seen in patients with Parkinson’s disease'. Together they form a unique fingerprint.

Cite this