Parkinson’s disease and multiple system atrophy have distinct -synuclein seed characteristics

Tritia R. Yamasaki, Brandon B. Holmes, Jennifer L. Furman, Dhruva D. Dhavale, Bryant W. Su, Eun Suk Song, Nigel J. Cairns, Paul T. Kotzbauer, Marc I. Diamond

Research output: Contribution to journalArticlepeer-review

96 Citations (SciVal)


Parkinson’s disease (PD) and multiple system atrophy (MSA) are distinct clinical syndromes characterized by the pathological accumulation of -synuclein (-syn) protein fibrils in neurons and glial cells. These disorders and other neurodegenerative diseases may progress via prion-like mechanisms. The prion model of propagation predicts the existence of “strains” that link pathological aggregate structure and neuropathology. Prion strains are aggregated conformers that stably propagate in vivo and cause disease with defined incubation times and patterns of neuropathology. Indeed, tau prions have been well defined, and research suggests that both -syn and -amyloid may also form strains. However, there is a lack of studies characterizing PD-versus MSA-derived -syn strains or demonstrating stable propagation of these unique conformers between cells or animals. To fill this gap, we used an assay based on FRET that exploits a HEK293T “biosensor” cell line stably expressing -syn (A53T)-CFP/YFP fusion proteins to detect -syn seeds in brain extracts from PD and MSA patients. Both soluble and insoluble fractions of MSA extracts had robust seeding activity, whereas only the insoluble fractions of PD extracts displayed seeding activity. The morphology of MSA-seeded inclusions differed from PD-seeded inclusions. These differences persisted upon propagation of aggregation to second-generation biosensor cells. We conclude that PD and MSA feature -syn conformers with very distinct biochemical properties that can be transmitted to -syn monomers in a cell system. These findings are consistent with the idea that distinct -syn strains underlie PD and MSA and offer possible directions for synucleinopathy diagnosis.

Original languageEnglish
Pages (from-to)1045-1058
Number of pages14
JournalJournal of Biological Chemistry
Issue number3
StatePublished - Jan 18 2019

Bibliographical note

Funding Information:
Acknowledgments—We thank John Cirrito, Washington University School of Medicine, Luke Bradley, Sidney Whiteheart, and Greg Ger-hardt, University of Kentucky, for the use of equipment and reagents. Human tissue samples were provided by Nigel Cairns with permission of Joel Perlmutter and the Movement Disorder Brain Bank at Washington University, St. Louis (supported by National Institutes of Health Grant NS075321, the Barnes Jewish Hospital Foundation (BJHF), the American Parkinson Disease Association (APDA) Advanced Research Center for Parkinson Disease at Washington University in St. Louis, the Greater St. Louis Chapter of the APDA, the Barnes Jewish Hospital Foundation (Elliot Stein Family Fund and Parkinson Disease Research Fund), and the Jo and Fred Oertli Fellowship Fund). The facility was supported by the NIH National Center for Advancing Translational Sciences through grant number KL2TR001996. Cell sorting services were provided by the Siteman Flow Cytometry Core and the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital.

Funding Information:
This work was supported by National Center for Advancing Translational Sci-ences Grant KL2 TR000116 at the University of Kentucky, T32 Training Grant 3857–77222B at the Washington University School of Medicine, a Mary E. Groff Charitable Trust Grant, and National Institute of Health NINDS Grants NS097799, NS075321, and NS110436. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2019 Yamasaki et al.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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