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

Author

Listed:
  • 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
    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
    University of Oxford)

  • Ronald Melki

    (CEA, Institut François Jacob (MIRCen) and CNRS, Laboratory of Neurodegenerative Diseases)

  • George K. Tofaris

    (University of Oxford)

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.

Suggested Citation

  • Benedict Tanudjojo & Samiha S. Shaikh & Alexis Fenyi & Luc Bousset & Devika Agarwal & Jade Marsh & Christos Zois & Sabrina Heman-Ackah & Roman Fischer & David Sims & Ronald Melki & George K. Tofaris, 2021. "Phenotypic manifestation of α-synuclein strains derived from Parkinson’s disease and multiple system atrophy in human dopaminergic neurons," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23682-z
    DOI: 10.1038/s41467-021-23682-z
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    Cited by:

    1. Wei Jiang & Qing Li & Ruofei Zhang & Jianru Li & Qianyu Lin & Jingyun Li & Xinyao Zhou & Xiyun Yan & Kelong Fan, 2023. "Chiral metal-organic frameworks incorporating nanozymes as neuroinflammation inhibitors for managing Parkinson’s disease," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Norihito Uemura & Nicholas P. Marotta & Jahan Ara & Emily S. Meymand & Bin Zhang & Hiroshi Kameda & Masato Koike & Kelvin C. Luk & John Q. Trojanowski & Virginia M.-Y. Lee, 2023. "α-Synuclein aggregates amplified from patient-derived Lewy bodies recapitulate Lewy body diseases in mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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