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Highly enriched hiPSC-derived midbrain dopaminergic neurons robustly models Parkinson’s disease

Gurvir S Virdi, Minee L Choi, Zhi Yao, James R Evans, Dilan Athauda, Daniela Melandri, Sergiy Sylantyev, Andrey Y Abramov, Rickie Patani, Sonia Gandhi
doi: https://doi.org/10.1101/2020.09.08.287797
Gurvir S Virdi
1The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
2Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK
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Minee L Choi
1The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
2Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK
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Zhi Yao
1The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
2Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK
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James R Evans
1The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
2Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK
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Dilan Athauda
1The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
2Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK
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Daniela Melandri
4Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK
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Sergiy Sylantyev
5Rowett Institute, University of Aberdeen, Ashgrove Rd West, Aberdeen, AB25 2ZD, UK
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Andrey Y Abramov
2Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK
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Rickie Patani
1The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
3Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK
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  • For correspondence: sonia.gandhi@crick.ac.uk
Sonia Gandhi
1The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
2Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK
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  • For correspondence: sonia.gandhi@crick.ac.uk
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Abstract

The development of human induced pluripotent stem cells (hiPSC) has greatly aided our ability to model neurodegenerative diseases. However, generation of midbrain dopaminergic (mDA) neurons is a major challenge and protocols are variable. Here, we developed a method to differentiate hiPSCs into enriched populations (>80%) of mDA neurons using only small molecules. We confirmed the identity of the mDA neurons using single-cell RNA-sequencing and detection of classical markers. Single-cell live imaging demonstrated neuronal calcium signalling and functional dopamine transport. Electrophysiology measures highlighted the ability to form synapses and networks in culture. Patient-specific hiPSC lines differentiated to produce functional mDA neurons that exhibit the hallmarks of synucleinopathy including: aggregate formation, oxidative stress as well as mitochondrial dysfunction and impaired lysosomal dynamics. In summary, we establish a robust differentiation paradigm to generate enriched mDA neurons from hiPSCs, which can be used to faithfully model key aspects of Parkinson’s disease (PD), providing the potential to further elucidate molecular mechanisms contributing to disease development.

Competing Interest Statement

The authors have declared no competing interest.

  • Abbreviations

    DAT
    Dopamine transporter
    FGF
    Fibroblast growth factor
    GDNF
    Glial cell-derived neurotrophic factor
    GIRK2
    G protein-activated inward rectifier potassium channel 2
    hiPSC
    Human induced pluripotent stem cells
    mDA
    Midbrain dopaminergic
    NPC
    Neuronal precursor cell
    Nurr1
    Nuclear receptor related-1 protein
    PD
    Parkinson’s disease
    ROCK
    Rho-associated protein kinase
    ROS
    Reactive oxygen species
    SHH
    Sonic hedgehog
    SIM
    Structured illumination microscopy
    SNCA
    Alpha-synuclein gene
    TH
    Tyrosine hydroxylase
    Wnt1
    Wingless-int1
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    Highly enriched hiPSC-derived midbrain dopaminergic neurons robustly models Parkinson’s disease
    Gurvir S Virdi, Minee L Choi, Zhi Yao, James R Evans, Dilan Athauda, Daniela Melandri, Sergiy Sylantyev, Andrey Y Abramov, Rickie Patani, Sonia Gandhi
    bioRxiv 2020.09.08.287797; doi: https://doi.org/10.1101/2020.09.08.287797
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    Highly enriched hiPSC-derived midbrain dopaminergic neurons robustly models Parkinson’s disease
    Gurvir S Virdi, Minee L Choi, Zhi Yao, James R Evans, Dilan Athauda, Daniela Melandri, Sergiy Sylantyev, Andrey Y Abramov, Rickie Patani, Sonia Gandhi
    bioRxiv 2020.09.08.287797; doi: https://doi.org/10.1101/2020.09.08.287797

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