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

Sebastian Schmidt, Malte D. Luecken, Dietrich Trümbach, Sina Hembach, Kristina M. Niedermeier, Nicole Wenck, Klaus Pflügler, Constantin Stautner, Anika Böttcher, Heiko Lickert, Ciro Ramirez-Suastegui, Ruhel Ahmad, Michael J. Ziller, Julia C. Fitzgerald, Viktoria Ruf, Wilma D. J. Berg, Allert J. Jonker, Thomas Gasser, Beate Winner, Jürgen Winkler, Daniela M. Vogt Weisenhorn, Florian Giesert (), Fabian J. Theis () and Wolfgang Wurst ()
Additional contact information
Sebastian Schmidt: Helmholtz Zentrum München
Malte D. Luecken: Helmholtz Zentrum München
Dietrich Trümbach: Helmholtz Zentrum München
Sina Hembach: Helmholtz Zentrum München
Kristina M. Niedermeier: Helmholtz Zentrum München
Nicole Wenck: Helmholtz Zentrum München
Klaus Pflügler: Helmholtz Zentrum München
Constantin Stautner: Helmholtz Zentrum München
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
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
Florian Giesert: Helmholtz Zentrum München
Fabian J. Theis: Helmholtz Zentrum München
Wolfgang Wurst: Helmholtz Zentrum München

Nature Communications, 2022, vol. 13, issue 1, 1-25

Abstract: 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32229-9

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DOI: 10.1038/s41467-022-32229-9

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