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alpha-Synuclein strains target distinct brain regions and cell types
Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada;Univ Toronto, Dept Biochem, Toronto, ON, Canada.ORCID iD: 0000-0001-7046-604X
Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada;Univ Toronto, Dept Biochem, Toronto, ON, Canada.
Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada;Univ Toronto, Dept Biochem, Toronto, ON, Canada.
Univ Cambridge, Dept Chem, Cambridge, England.
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2020 (English)In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 23, p. 21-31Article in journal (Refereed) Published
Abstract [en]

The clinical and pathological differences between synucleinopathies such as Parkinson's disease and multiple system atrophy have been postulated to stem from unique strains of alpha-synuclein aggregates, akin to what occurs in prion diseases. Here we demonstrate that inoculation of transgenic mice with different strains of recombinant or brain-derived alpha-synuclein aggregates produces clinically and pathologically distinct diseases. Strain-specific differences were observed in the signs of neurological illness, time to disease onset, morphology of cerebral alpha-synuclein deposits and the conformational properties of the induced aggregates. Moreover, different strains targeted distinct cellular populations and cell types within the brain, recapitulating the selective targeting observed among human synucleinopathies. Strain-specific clinical, pathological and biochemical differences were faithfully maintained after serial passaging, which implies that alpha-synuclein propagates via prion-like conformational templating. Thus, pathogenic alpha-synuclein exhibits key hallmarks of prion strains, which provides evidence that disease heterogeneity among the synucleinopathies is caused by distinct alpha-synuclein strains.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2020. Vol. 23, p. 21-31
National Category
Neurosciences Neurology
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URN: urn:nbn:se:uu:diva-406215DOI: 10.1038/s41593-019-0541-xISI: 000507601600004PubMedID: 31792467OAI: oai:DiVA.org:uu-406215DiVA, id: diva2:1412415
Funder
EU, European Research Council, 669237Available from: 2020-03-06 Created: 2020-03-06 Last updated: 2020-03-06Bibliographically approved

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