{"id":"doi:10.1038/s41467-021-23682-z","kind":"article","title":"Phenotypic manifestation of α-synuclein strains derived from Parkinson's disease and multiple system atrophy in human dopaminergic neurons","authors":["Tanudjojo B","Shaikh SS","Fenyi A","Bousset L","Agarwal D","Marsh J","Zois C","Heman-Ackah S","Fischer R","Sims D","Melki R","Tofaris GK"],"author_count":12,"year":2021,"published":"2021-06-21","venue":"Nature communications","cited_by":79,"doi":"10.1038/s41467-021-23682-z","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41467-021-23682-z","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41467-021-23682-z","updated":null,"pmid":"34155194","pmcid":"PMC8217249","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC8217249/pdf","abstract":"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.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Phenotypic manifestation of α-synuclein strains derived from Parkinson's disease and multiple system atrophy in human dopaminergic neurons\" by Tanudjojo B, Shaikh SS, Fenyi A et al., https://doi.org/10.1038/s41467-021-23682-z, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"gene-cell-therapy","name":"Gene & Cell Therapy","domain_slug":"medicine"}],"cited_in_dossiers":[]}