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

Wei-Li  Kuan; Katherine  Stott; Xiaoling He; Tobias Wood; Sujeong Yang; Jessica  Kwok; Katie Hall; Yanyan Zhao; Ole Tietz; Franklin Aigbirhio; Anthony Vernon; Roger Barker

doi:10.1038/s41380-019-0608-9

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

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

University of Cambridge

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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 language	English
Pages (from-to)	556–567
Number of pages	12
Journal	Molecular Psychiatry
Volume	26
Issue number	2
Early online date	23 Nov 2019
DOIs	https://doi.org/10.1038/s41380-019-0608-9
Publication status	Published - 1 Feb 2021

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title = "Systemic α-synuclein injection triggers selective neuronal pathology as seen in patients with Parkinson{\textquoteright}s disease",

abstract = "Parkinson{\textquoteright}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.",

author = "Wei-Li Kuan and Katherine Stott and Xiaoling He and Tobias Wood and Sujeong Yang and Jessica Kwok and Katie Hall and Yanyan Zhao and Ole Tietz and Franklin Aigbirhio and Anthony Vernon and Roger Barker",

note = "Funding Information: Acknowledgements This study was funded by the Rosetrees Trust (CM234), as well as a fellowship awarded to WLK by the Medical Research Council (MR/S005528/1). RAB 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). JCFK is supported by Wings for Life Foundation. SJY is supported by Alzheimer{\textquoteright}s Research UK (ARUK-RF2016A-1). ACV 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{\textquoteright}s Seventh Framework Programme for research, technological development, and demonstration under grant agreement no. 242003. The authors would like to thank Prof. MG Spillantini, Dr J Xia, and Dr JN Skepper for their help in the analysis of the experiments. Publisher Copyright: {\textcopyright} 2019, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

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doi = "10.1038/s41380-019-0608-9",

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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

AU - Yang, Sujeong

AU - Kwok, Jessica

AU - Hall, Katie

AU - Zhao, Yanyan

AU - Tietz, Ole

AU - Aigbirhio, Franklin

AU - Vernon, Anthony

AU - Barker, Roger

N1 - Funding Information: Acknowledgements This study was funded by the Rosetrees Trust (CM234), as well as a fellowship awarded to WLK by the Medical Research Council (MR/S005528/1). RAB 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). JCFK is supported by Wings for Life Foundation. SJY is supported by Alzheimer’s Research UK (ARUK-RF2016A-1). ACV 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. MG Spillantini, Dr J Xia, and Dr JN Skepper for their help in the analysis of the experiments. Publisher Copyright: © 2019, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

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.

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DO - 10.1038/s41380-019-0608-9

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EP - 567

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 2

ER -

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

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