Although -synucleinis implicated in the pathogenesis of Parkinsons disease and related disorders, it remains unclear whether specific conformations or levels of -synuclein assemblies are toxic and how they cause progressive loss of human dopaminergic neurons. To address this issue, we used iPSC-derived dopaminergic neurons with a-synuclein triplication or controls where endogenous -synuclein was imprinted into synthetic or disease-relevant conformations. We used -synuclein fibrils generated de novo or amplified from homogenates of brains affected with Parkinsons disease (n=3) .We found that a 2.5-fold increase in -synuclein levels in -synuclein gene triplication neurons promoted seeded aggregation in a dose and time-dependent fashion, which was associated with a further increase in -synuclein gene expression.Transcriptomic analysis and isogenic correction of -synuclein triplication revealed that intraneuronal -synuclein levels solely and sufficiently explained vulnerability to cell death. SOURCE: Devika Agarwal (devika.agarwal@ndcls.ox.ac.uk) - Centre for Computational Biology University of Oxford

Pluto Bioinformatics

GSE149632: Phenotypic manifestation of alpha-synuclein strains from Parkinsons disease and multiple system atrophy in human dopaminergic neruons