%0 Journal Article
%T Phenotypic manifestation of α-synuclein strains derived from Parkinson’s disease and multiple system atrophy in human dopaminergic neurons
%V 12
%N 1
%P 3817
%U http://www.nature.com/articles/s41467-021-23682-z
%X 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.
%G en
%J Nature Communications
%A Tanudjojo, Benedict
%A Shaikh, Samiha S.
%A Fenyi, Alexis
%A Bousset, Luc
%A Agarwal, Devika
%A Marsh, Jade
%A Zois, Christos
%A Heman-Ackah, Sabrina
%A Fischer, Roman
%A Sims, David
%A Melki, Ronald
%A Tofaris, George K.
%D 12/2021
%K highlight
peer-reviewed