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Systemic α-synuclein injection triggers selective neuronal pathology as seen in patients with Parkinson's disease
WL. Kuan, K. Stott, X. He, TC. Wood, S. Yang, JCF. Kwok, K. Hall, Y. Zhao, O. Tietz, FI. Aigbirhio, AC. Vernon, RA. Barker
Language English Country Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
MR/K02308X/1
Medical Research Council - United Kingdom
MR/R015724/1
Medical Research Council - United Kingdom
MR/N025377/1
Medical Research Council - United Kingdom
MR/S005528/1
Medical Research Council - United Kingdom
203151
Wellcome Trust - United Kingdom
MC_PC_12009
Medical Research Council - United Kingdom
MR/N026063/1
Medical Research Council - United Kingdom
Wellcome Trust - United Kingdom
Department of Health - United Kingdom
NLK
ProQuest Central
from 2000-01-01 to 1 year ago
Open Access Digital Library
from 1997-01-01
Health & Medicine (ProQuest)
from 2000-01-01 to 1 year ago
Psychology Database (ProQuest)
from 2000-01-01 to 1 year ago
- MeSH
- alpha-Synuclein metabolism MeSH
- Humans MeSH
- Brain metabolism MeSH
- Neurons metabolism MeSH
- Parkinson Disease * MeSH
- Enteric Nervous System * metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
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
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
References provided by Crossref.org
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