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Modeling alpha-synuclein pathology in a human brain-chip to assess blood-brain barrier disruption

Author

Listed:
  • Iosif Pediaditakis

    (Emulate Inc., 27 Drydock Avenue
    Serqet Therapeutics, Inc. 55 Cambridge Parkway)

  • Konstantia R. Kodella

    (Emulate Inc., 27 Drydock Avenue)

  • Dimitris V. Manatakis

    (Emulate Inc., 27 Drydock Avenue)

  • Christopher Y. Le

    (Emulate Inc., 27 Drydock Avenue)

  • Chris D. Hinojosa

    (Emulate Inc., 27 Drydock Avenue)

  • William Tien-Street

    (Emulate Inc., 27 Drydock Avenue)

  • Elias S. Manolakos

    (National and Kapodistrian University of Athens
    Northeastern University, Bouvé College of Health Sciences)

  • Kostas Vekrellis

    (Biomedical Research Foundation of Academy of Athens)

  • Geraldine A. Hamilton

    (Emulate Inc., 27 Drydock Avenue)

  • Lorna Ewart

    (Emulate Inc., 27 Drydock Avenue)

  • Lee L. Rubin

    (Harvard University
    Harvard Stem Cell Institute
    Broad Institute of Massachusetts Institute of Technology and Harvard)

  • Katia Karalis

    (Emulate Inc., 27 Drydock Avenue
    Endocrine Division, Children’s Hospital, Harvard Medical School
    Regeneron Pharmaceuticals)

Abstract

Parkinson’s disease and related synucleinopathies are characterized by the abnormal accumulation of alpha-synuclein aggregates, loss of dopaminergic neurons, and gliosis of the substantia nigra. Although clinical evidence and in vitro studies indicate disruption of the Blood-Brain Barrier in Parkinson’s disease, the mechanisms mediating the endothelial dysfunction is not well understood. Here we leveraged the Organs-on-Chips technology to develop a human Brain-Chip representative of the substantia nigra area of the brain containing dopaminergic neurons, astrocytes, microglia, pericytes, and microvascular brain endothelial cells, cultured under fluid flow. Our αSyn fibril-induced model was capable of reproducing several key aspects of Parkinson’s disease, including accumulation of phosphorylated αSyn (pSer129-αSyn), mitochondrial impairment, neuroinflammation, and compromised barrier function. This model may enable research into the dynamics of cell-cell interactions in human synucleinopathies and serve as a testing platform for target identification and validation of novel therapeutics.

Suggested Citation

  • Iosif Pediaditakis & Konstantia R. Kodella & Dimitris V. Manatakis & Christopher Y. Le & Chris D. Hinojosa & William Tien-Street & Elias S. Manolakos & Kostas Vekrellis & Geraldine A. Hamilton & Lorna, 2021. "Modeling alpha-synuclein pathology in a human brain-chip to assess blood-brain barrier disruption," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26066-5
    DOI: 10.1038/s41467-021-26066-5
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    1. Tae-Eun Park & Nur Mustafaoglu & Anna Herland & Ryan Hasselkus & Robert Mannix & Edward A. FitzGerald & Rachelle Prantil-Baun & Alexander Watters & Olivier Henry & Maximilian Benz & Henry Sanchez & He, 2019. "Hypoxia-enhanced Blood-Brain Barrier Chip recapitulates human barrier function and shuttling of drugs and antibodies," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    2. Paul T E Cusack, 2020. "The Human Brain," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 31(3), pages 24261-24266, October.
    3. W. Peelaerts & L. Bousset & A. Van der Perren & A. Moskalyuk & R. Pulizzi & M. Giugliano & C. Van den Haute & R. Melki & V. Baekelandt, 2015. "α-Synuclein strains cause distinct synucleinopathies after local and systemic administration," Nature, Nature, vol. 522(7556), pages 340-344, June.
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    1. Lei Tang & Nana Xu & Mengyao Huang & Wei Yi & Xuan Sang & Mingting Shao & Ye Li & Zhao-zhe Hao & Ruifeng Liu & Yuhui Shen & Feng Yue & Xialin Liu & Chuan Xu & Sheng Liu, 2023. "A primate nigrostriatal atlas of neuronal vulnerability and resilience in a model of Parkinson’s disease," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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