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Discriminating alpha-synuclein strains in Parkinsons disease and multiple system atrophy
Univ Texas Houston, TX 77004 USA.
Univ Texas Houston, TX 77004 USA.
Univ Texas Houston, TX 77004 USA.
Univ Texas Houston, TX 77004 USA.
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2020 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687Article in journal (Refereed) Epub ahead of print
Abstract [en]

Synucleinopathies are neurodegenerative diseases that are associated with the misfolding and aggregation of alpha-synuclein, including Parkinsons disease, dementia with Lewy bodies and multiple system atrophy(1). Clinically, it is challenging to differentiate Parkinsons disease and multiple system atrophy, especially at the early stages of disease(2). Aggregates of alpha-synuclein in distinct synucleinopathies have been proposed to represent different conformational strains of alpha-synuclein that can self-propagate and spread from cell to cell(3-6). Protein misfolding cyclic amplification (PMCA) is a technique that has previously been used to detect alpha-synuclein aggregates in samples of cerebrospinal fluid with high sensitivity and specificity(7,8). Here we show that the alpha-synuclein-PMCA assay can discriminate between samples of cerebrospinal fluid from patients diagnosed with Parkinsons disease and samples from patients with multiple system atrophy, with an overall sensitivity of 95.4%. We used a combination of biochemical, biophysical and biological methods to analyse the product of alpha-synuclein-PMCA, and found that the characteristics of the alpha-synuclein aggregates in the cerebrospinal fluid could be used to readily distinguish between Parkinsons disease and multiple system atrophy. We also found that the properties of aggregates that were amplified from the cerebrospinal fluid were similar to those of aggregates that were amplified from the brain. These findings suggest that alpha-synuclein aggregates that are associated with Parkinsons disease and multiple system atrophy correspond to different conformational strains of alpha-synuclein, which can be amplified and detected by alpha-synuclein-PMCA. Our results may help to improve our understanding of the mechanism of alpha-synuclein misfolding and the structures of the aggregates that are implicated in different synucleinopathies, and may also enable the development of a biochemical assay to discriminate between Parkinsons disease and multiple system atrophy. Protein misfolding cyclic amplification (PMCA) technology can discriminate between patients with Parkinsons disease and patients with multiple system atrophy on the basis of the characteristics of the alpha-synuclein aggregates in the cerebrospinal fluid.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2020.
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Neurosciences
Identifiers
URN: urn:nbn:se:liu:diva-163879DOI: 10.1038/s41586-020-1984-7ISI: 000511285700005PubMedID: 32025029OAI: oai:DiVA.org:liu-163879DiVA, id: diva2:1395678
Note

Funding Agencies|Michael J. Fox Foundation for Parkinsons disease; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P01NS44233, U54NS065736, K23NS075141, R01 FD004789, R01 NS092625, R01AG055053, R01AG061069]; Department of DefenseUnited States Department of Defense; Swedish Research CouncilSwedish Research Council [2016-00748]; Mayo Funds; [RO1 NS094535]

Available from: 2020-02-24 Created: 2020-02-24 Last updated: 2020-02-24

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