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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

. 2021 ; 26 (2) : 556-567. [pub] 20191122

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc21019362

Grantová podpora
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

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.

Citace poskytuje Crossref.org

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