TY - JOUR
T1 - Systemic α-synuclein injection triggers selective neuronal pathology as seen in patients with Parkinson’s disease
AU - Kuan, Wei-Li
AU - Stott, Katherine
AU - He, Xiaoling
AU - Wood, Tobias C.
AU - Yang, Sujeong
AU - Kwok, Jessica C.F.
AU - Hall, Katie
AU - Zhao, Yanyan
AU - Tietz, Ole
AU - Aigbirhio, Franklin I.
AU - Vernon, Anthony C.
AU - Barker, Roger A.
N1 - 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.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85075429616&partnerID=8YFLogxK
U2 - 10.1038/s41380-019-0608-9
DO - 10.1038/s41380-019-0608-9
M3 - Article
C2 - 31758091
AN - SCOPUS:85075429616
VL - 26
SP - 556
EP - 567
JO - Molecular Psychiatry
JF - Molecular Psychiatry
SN - 1359-4184
IS - 2
ER -