Assembly of α-synuclein and neurodegeneration in the central nervous system of heterozygous M83 mice following the peripheral administration of α-synuclein seeds.

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cam.issuedOnline2021-11-24
dc.contributor.authorMacdonald, Jennifer A
dc.contributor.authorChen, John L
dc.contributor.authorMasuda-Suzukake, Masami
dc.contributor.authorSchweighauser, Manuel
dc.contributor.authorJaunmuktane, Zane
dc.contributor.authorWarner, Thomas
dc.contributor.authorHolton, Janice L
dc.contributor.authorGrossman, Annabelle
dc.contributor.authorBerks, Richard
dc.contributor.authorLavenir, Isabelle
dc.contributor.authorGoedert, Michel
dc.date.accessioned2021-11-24T16:21:47Z
dc.date.available2021-11-24T16:21:47Z
dc.date.issued2021-11-24
dc.date.submitted2021-09-15
dc.date.updated2021-11-24T16:21:46Z
dc.description.abstractPeripheral 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.
dc.identifier.doi10.17863/CAM.78474
dc.identifier.eissn2051-5960
dc.identifier.issn2051-5960
dc.identifier.others40478-021-01291-7
dc.identifier.other1291
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/331029
dc.languageen
dc.publisherSpringer Science and Business Media LLC
dc.subjectResearch
dc.subjectα-Synuclein
dc.subjectMultiple system atrophy
dc.subjectSeeded assembly
dc.subjectNeurodegeneration
dc.subjectMicroglia
dc.titleAssembly of α-synuclein and neurodegeneration in the central nervous system of heterozygous M83 mice following the peripheral administration of α-synuclein seeds.
dc.typeArticle
dcterms.dateAccepted2021-11-08
prism.issueIdentifier1
prism.publicationNameActa Neuropathol Commun
prism.volume9
pubs.funder-project-idUK Medical Research Council (MC_U105184291)
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1186/s40478-021-01291-7
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