Seeded propagation of alpha-synuclein aggregation in mouse brain using protein misfolding cyclic amplification

Alpha-synuclein (-syn) protein aggregation is associated with several neurodegenerative disorders collectively referred to as synucleinopathies, including Parkinson disease. We used protein misfolding cyclic amplification (PMCA) to study -syn aggregation in brain homogenates of wild-type or transgenic mice expressing normal (D line) or A53T mutant (M83 line) human -syn. We found that sonication-incubation cycles of M83 mouse brain gradually produce large quantities of SDS-resistant -syn aggregates, involving both human and mouse proteins. These PMCA products, containing partially proteinase K resistant -syn species, are competent to accelerate the onset of neurological symptoms after intracerebral inoculation to young M83 mice and to seed aggregate formation of -syn following PMCA, including in D and wild-type mouse brain substrates. Our data indicate that similar to prions, PMCA can reproduce some characteristics of -syn aggregation and seeded-propagation in vitro in a complex milieu. This opens new opportunities for the molecular study of synucleinopathies.