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 journalArticle

8 Citations (Scopus)

Abstract

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 (US)
Pages (from-to)1045-1058
Number of pages14
JournalJournal of Biological Chemistry
Volume294
Issue number3
DOIs
StatePublished - Jan 1 2019

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Synucleins
Multiple System Atrophy
Parkinson Disease
Seed
Seeds
Prions
Biosensing Techniques
Biosensors
Neurodegenerative diseases
Amyloid
Neuroglia
Neurodegenerative Diseases
Proteins
Neurons
Assays
Brain
Animals
Fusion reactions
Agglomeration
Monomers

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Parkinson’s disease and multiple system atrophy have distinct -synuclein seed characteristics. / Yamasaki, Tritia R.; Holmes, Brandon B.; Furman, Jennifer L.; Dhavale, Dhruva D.; Su, Bryant W.; Song, Eun Suk; Cairns, Nigel J.; Kotzbauer, Paul T.; Diamond, Marc I.

In: Journal of Biological Chemistry, Vol. 294, No. 3, 01.01.2019, p. 1045-1058.

Research output: Contribution to journalArticle

Yamasaki, TR, Holmes, BB, Furman, JL, Dhavale, DD, Su, BW, Song, ES, Cairns, NJ, Kotzbauer, PT & Diamond, MI 2019, 'Parkinson’s disease and multiple system atrophy have distinct -synuclein seed characteristics', Journal of Biological Chemistry, vol. 294, no. 3, pp. 1045-1058. https://doi.org/10.1074/jbc.RA118.004471
Yamasaki, Tritia R. ; Holmes, Brandon B. ; Furman, Jennifer L. ; Dhavale, Dhruva D. ; Su, Bryant W. ; Song, Eun Suk ; Cairns, Nigel J. ; Kotzbauer, Paul T. ; Diamond, Marc I. / Parkinson’s disease and multiple system atrophy have distinct -synuclein seed characteristics. In: Journal of Biological Chemistry. 2019 ; Vol. 294, No. 3. pp. 1045-1058.
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AU - Su, Bryant W.

AU - Song, Eun Suk

AU - Cairns, Nigel J.

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AU - Diamond, Marc I

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AB - 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.

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