Published June 21, 2022 | Version v2
Dataset Open

Source Data files for: Primary cilia and SHH signaling impairments in human and mouse models of Parkinson's disease

Authors/Creators

  • 1. Institute of Developmental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
  • 2. Institute of Computational Biology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
  • 3. Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
  • 4. Max Planck Institute of Psychiatry, Munich 80804, Germany
  • 5. Department of Psychiatry, University of Münster, 48149 Münster, Germany
  • 6. Department of Neurodegenerative Diseases, Center of Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Straße 3, 72076 Tübingen, Germany
  • 7. Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität Munich, Feodor-Lynen-Str. 23, 81377 Munich, Germany
  • 8. Section Clinical Neuroanatomy and Biobanking (CNAB), Department of Anatomy and Neurosciences, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081HV, Amsterdam, The Netherlands
  • 9. Department of Stem Cell Biology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Glückstrasse 6, 91054 Erlangen, Germany
  • 10. Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054 Erlangen, Germany

Description

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 an increased SHH signal transduction. Inhibition of this pathway rescues the alterations in PC morphology and mitochondrial dysfunction. Thus, increased SHH activity due to ciliary dysfunction is needed for the development of pathoetiological phenotypes observed in sPD, like mitochondrial dysfunction. In sum, altered PC function is part of early PD pathoetiology and inhibiting the overactive SHH signaling is a potential neuroprotective therapy.

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