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Primary cilia and SHH signaling impairments in human and mouse models of Parkinson’s disease

Author

Listed:
  • Sebastian Schmidt

    (Helmholtz Zentrum München
    Technical University of Munich)

  • Malte D. Luecken

    (Helmholtz Zentrum München)

  • Dietrich Trümbach

    (Helmholtz Zentrum München
    Helmholtz Zentrum München)

  • Sina Hembach

    (Helmholtz Zentrum München
    Technical University of Munich)

  • Kristina M. Niedermeier

    (Helmholtz Zentrum München
    Technical University of Munich)

  • Nicole Wenck

    (Helmholtz Zentrum München
    Technical University of Munich)

  • Klaus Pflügler

    (Helmholtz Zentrum München
    Technical University of Munich)

  • Constantin Stautner

    (Helmholtz Zentrum München
    Technical University of Munich)

  • Anika Böttcher

    (Helmholtz Zentrum München)

  • Heiko Lickert

    (Helmholtz Zentrum München)

  • Ciro Ramirez-Suastegui

    (Helmholtz Zentrum München)

  • Ruhel Ahmad

    (Max Planck Institute of Psychiatry)

  • Michael J. Ziller

    (University of Münster)

  • Julia C. Fitzgerald

    (University of Tübingen)

  • Viktoria Ruf

    (Ludwig-Maximilians-Universität Munich
    Munich Cluster of Systems Neurology (SyNergy))

  • Wilma D. J. Berg

    (Amsterdam UMC, Vrije Universiteit Amsterdam)

  • Allert J. Jonker

    (Amsterdam UMC, Vrije Universiteit Amsterdam)

  • Thomas Gasser

    (University of Tübingen)

  • Beate Winner

    (University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU))

  • Jürgen Winkler

    (University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU))

  • Daniela M. Vogt Weisenhorn

    (Helmholtz Zentrum München
    Technical University of Munich)

  • Florian Giesert

    (Helmholtz Zentrum München)

  • Fabian J. Theis

    (Helmholtz Zentrum München
    Technische Universität München)

  • Wolfgang Wurst

    (Helmholtz Zentrum München
    Technical University of Munich
    Munich Cluster of Systems Neurology (SyNergy)
    German Center for Neurodegenerative Diseases (DZNE) site Munich)

Abstract

Parkinson’s disease (PD) as a progressive neurodegenerative disorder arises from multiple genetic and environmental factors. However, underlying pathological mechanisms remain poorly understood. Using multiplexed single-cell transcriptomics, we analyze human neural precursor cells (hNPCs) from sporadic PD (sPD) patients. Alterations in gene expression appear in pathways related to primary cilia (PC). Accordingly, in these hiPSC-derived hNPCs and neurons, we observe a shortening of PC. Additionally, we detect a shortening of PC in PINK1-deficient human cellular and mouse models of familial PD. Furthermore, in sPD models, the shortening of PC is accompanied by increased Sonic Hedgehog (SHH) signal transduction. Inhibition of this pathway rescues the alterations in PC morphology and mitochondrial dysfunction. Thus, increased SHH activity due to ciliary dysfunction may be required for the development of pathoetiological phenotypes observed in sPD like mitochondrial dysfunction. Inhibiting overactive SHH signaling may be a potential neuroprotective therapy for sPD.

Suggested Citation

  • Sebastian Schmidt & Malte D. Luecken & Dietrich Trümbach & Sina Hembach & Kristina M. Niedermeier & Nicole Wenck & Klaus Pflügler & Constantin Stautner & Anika Böttcher & Heiko Lickert & Ciro Ramirez-, 2022. "Primary cilia and SHH signaling impairments in human and mouse models of Parkinson’s disease," Nature Communications, Nature, vol. 13(1), pages 1-25, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32229-9
    DOI: 10.1038/s41467-022-32229-9
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    References listed on IDEAS

    as
    1. Qian Wang & Yuanxi Zhang & Minghui Wang & Won-Min Song & Qi Shen & Andrew McKenzie & Insup Choi & Xianxiao Zhou & Ping-Yue Pan & Zhenyu Yue & Bin Zhang, 2019. "The landscape of multiscale transcriptomic networks and key regulators in Parkinson’s disease," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    2. M. Büttner & J. Ostner & C. L. Müller & F. J. Theis & B. Schubert, 2021. "scCODA is a Bayesian model for compositional single-cell data analysis," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    3. Richard L. Carpenter & Haimanti Ray, 2019. "Safety and Tolerability of Sonic Hedgehog Pathway Inhibitors in Cancer," Drug Safety, Springer, vol. 42(2), pages 263-279, February.
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    Cited by:

    1. Sebastian Schmidt & Constantin Stautner & Duc Tung Vu & Alexander Heinz & Martin Regensburger & Ozge Karayel & Dietrich Trümbach & Anna Artati & Sabine Kaltenhäuser & Mohamed Zakaria Nassef & Sina Hem, 2023. "A reversible state of hypometabolism in a human cellular model of sporadic Parkinson’s disease," Nature Communications, Nature, vol. 14(1), pages 1-24, December.

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