@article{tanudjojo_phenotypic_2021,
	title = {Phenotypic manifestation of α-synuclein strains derived from Parkinson’s disease and multiple system atrophy in human dopaminergic neurons},
	volume = {12},
	issn = {2041-1723},
	url = {http://www.nature.com/articles/s41467-021-23682-z},
	doi = {10.1038/s41467-021-23682-z},
	abstract = {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.},
	pages = {3817},
	number = {1},
	journaltitle = {Nature Communications},
	shortjournal = {Nat Commun},
	author = {Tanudjojo, Benedict and Shaikh, Samiha S. and Fenyi, Alexis and Bousset, Luc and Agarwal, Devika and Marsh, Jade and Zois, Christos and Heman-Ackah, Sabrina and Fischer, Roman and Sims, David and Melki, Ronald and Tofaris, George K.},
	urldate = {2021-06-22},
	date = {2021-12},
	langid = {english},
	keywords = {highlight, peer-reviewed},
}