Phenotypic manifestation of α-synuclein strains derived from Parkinson’s disease and multiple system atrophy in human dopaminergic neurons

Benedict Tanudjojo, Samiha S. Shaikh, Alexis Fenyi, Luc Bousset, Devika Agarwal, Jade Marsh, Christos Zois, Sabrina Heman-Ackah, Roman Fischer, David Sims, Ronald Melki and George K. Tofaris ()
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Benedict Tanudjojo: University of Oxford
Samiha S. Shaikh: University of Oxford
Alexis Fenyi: CEA, Institut François Jacob (MIRCen) and CNRS, Laboratory of Neurodegenerative Diseases
Luc Bousset: CEA, Institut François Jacob (MIRCen) and CNRS, Laboratory of Neurodegenerative Diseases
Devika Agarwal: University of Oxford
Jade Marsh: University of Oxford
Christos Zois: University of Oxford
Sabrina Heman-Ackah: University of Pennsylvania
Roman Fischer: University of Oxford
David Sims: University of Oxford
Ronald Melki: CEA, Institut François Jacob (MIRCen) and CNRS, Laboratory of Neurodegenerative Diseases
George K. Tofaris: University of Oxford

Nature Communications, 2021, vol. 12, issue 1, 1-16

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.

Date: 2021
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DOI: 10.1038/s41467-021-23682-z

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