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α-Synuclein is critical in the pathogenesis of Parkinson's disease and related disorders, yet it remains unclear how its aggregation causes degeneration of human dopaminergic neurons. In this study, we induced α-synuclein aggregation in human iPSC-derived dopaminergic neurons using fibrils generated de novo or amplified in the presence of brain homogenates from Parkinson's disease or multiple system atrophy. Increased α-synuclein monomer levels promote seeded aggregation in a dose and time-dependent manner, which is associated with a further increase in α-synuclein gene expression. Progressive neuronal death is observed with brain-amplified fibrils and reversed by reduction of intraneuronal α-synuclein abundance. We identified 56 proteins differentially interacting with aggregates triggered by brain-amplified fibrils, including evasion of Parkinson's disease-associated deglycase DJ-1. Knockout of DJ-1 in iPSC-derived dopaminergic neurons enhance fibril-induced aggregation and neuronal death. Taken together, our results show that the toxicity of α-synuclein strains depends on aggregate burden, which is determined by monomer levels and conformation which dictates differential interactomes. Our study demonstrates how Parkinson's disease-associated genes influence the phenotypic manifestation of strains in human neurons.

Original publication

DOI

10.1038/s41467-021-23682-z

Type

Journal article

Journal

Nat Commun

Publication Date

21/06/2021

Volume

12

Keywords

Brain, Cell Death, Dopaminergic Neurons, Humans, Induced Pluripotent Stem Cells, Multiple System Atrophy, Parkinson Disease, Phenotype, Protein Aggregates, Protein Aggregation, Pathological, Protein Conformation, Protein Deglycase DJ-1, Protein Interaction Mapping, alpha-Synuclein