Macdonald, JA;
Chen, JL;
Masuda-Suzukake, M;
Schweighauser, M;
Jaunmuktane, Z;
Warner, T;
Holton, JL;
... Goedert, M; + view all
(2021)
Assembly of alpha-synuclein and neurodegeneration in the central nervous system of heterozygous M83 mice following the peripheral administration of alpha-synuclein seeds.
Acta Neuropathologica Communications
, 9
, Article 189. 10.1186/s40478-021-01291-7.
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Abstract
Peripheral administration (oral, intranasal, intraperitoneal, intravenous) of assembled A53T α-synuclein induced synucleinopathy in heterozygous mice transgenic for human mutant A53T α-synuclein (line M83). The same was the case when cerebellar extracts from a case of multiple system atrophy with type II α-synuclein filaments were administered intraperitoneally, intravenously or intramuscularly. We observed abundant immunoreactivity for pS129 α-synuclein in nerve cells and severe motor impairment, resulting in hindlimb paralysis and shortened lifespan. Filaments immunoreactive for pS129 α-synuclein were in evidence. A 70% loss of motor neurons was present five months after an intraperitoneal injection of assembled A53T α-synuclein or cerebellar extract with type II α-synuclein filaments from an individual with a neuropathologically confirmed diagnosis of multiple system atrophy. Microglial cells changed from a predominantly ramified to a dystrophic appearance. Taken together, these findings establish a close relationship between the formation of α-synuclein inclusions in nerve cells and neurodegeneration, accompanied by a shift in microglial cell morphology. Propagation of α-synuclein inclusions depended on the characteristics of both seeds and transgenically expressed protein.
| Type: | Article |
|---|---|
| Title: | Assembly of alpha-synuclein and neurodegeneration in the central nervous system of heterozygous M83 mice following the peripheral administration of alpha-synuclein seeds |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/s40478-021-01291-7 |
| Publisher version: | https://doi.org/10.1186/s40478-021-01291-7 |
| Language: | English |
| Additional information: | © The Author(s) 2021, corrected publication 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Neurosciences, Neurosciences & Neurology, alpha-Synuclein, Multiple system atrophy, Seeded assembly, Neurodegeneration, Microglia, PARKINSONS-DISEASE, GASTROINTESTINAL-TRACT, LEWY BODIES, BRAIN, PATHOLOGY, TRANSMISSION, PROPAGATION, DEMENTIA, PRIONS, SPREAD |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10140008 |
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