Parkinson's disease and multiple system atrophy have distinct α-synuclein seed characteristics.

Parkinson's disease (PD) and multiple system atrophy (MSA) are distinct clinical syndromes characterized by the pathological accumulation of α-synuclein (α-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 α-syn and β-amyloid may also form strains. However, there is a lack of studies characterizing PD- versus MSA-derived α-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 α-syn (A53T)-CFP/YFP fusion proteins to detect α-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 α-syn conformers with very distinct biochemical properties that can be transmitted to α-syn monomers in a cell system. These findings are consistent with the idea that distinct α-syn strains underlie PD and MSA and offer possible directions for synucleinopathy diagnosis.

Yamasaki TR ，Holmes BB ，Furman JL ，Dhavale DD ，Su BW ，Song ES ，Cairns NJ ，Kotzbauer PT ，Diamond MI ... -  《-》

Overexpression of α-Synuclein by Oligodendrocytes in Transgenic Mice Does Not Recapitulate the Fibrillar Aggregation Seen in Multiple System Atrophy.

Laferrière F ，He X ，Zinghirino F ，Doudnikoff E ，Faggiani E ，Meissner WG ，Bezard E ，De Giorgi F ，Ichas F ... -  《Cells》

Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism.

Prusiner SB ，Woerman AL ，Mordes DA ，Watts JC ，Rampersaud R ，Berry DB ，Patel S ，Oehler A ，Lowe JK ，Kravitz SN ，Geschwind DH ，Glidden DV ，Halliday GM ，Middleton LT ，Gentleman SM ，Grinberg LT ，Giles K ... -  《-》

Potent prion-like behaviors of pathogenic α-synuclein and evaluation of inactivation methods.

Tarutani A ，Arai T ，Murayama S ，Hisanaga SI ，Hasegawa M ... -  《Acta Neuropathologica Communications》

Silver staining (Campbell-Switzer) of neuronal α-synuclein assemblies induced by multiple system atrophy and Parkinson's disease brain extracts in transgenic mice.

Lavenir I ，Passarella D ，Masuda-Suzukake M ，Curry A ，Holton JL ，Ghetti B ，Goedert M ... -  《-》