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

Schmidt S, Luecken MD, Truembach D, Hembach S, Niedermeier KM, Wenck N, Pfluegler K, Stautner C, Boettcher A, Lickert H, Ramirez-Suastegui C, Ahmad R, Ziller MJ, Fitzgerald JC, Ruf V, Van De Berg WDJ, Jonker AJ, Gasser T, Winner B, Winkler J, Weisenhorn DMV, Giesert F, Theis FJ, Wurst W (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 13

Journal Issue: 1

DOI: 10.1038/s41467-022-32229-9

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.

Authors with CRIS profile

Beate Winner Professur für Stammzell-Modelle seltener neuraler Erkrankungen Jürgen Winkler Professur für Molekulare Neurologie

Involved external institutions

Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Max-Planck-Institut für Psychiatrie (Deutsche Forschungsanstalt für Psychiatrie) DE Germany (DE) Westfälische Wilhelms-Universität (WWU) Münster DE Germany (DE) Eberhard Karls Universität Tübingen DE Germany (DE) Vrije Universiteit Amsterdam (VU) / University Amsterdam NL Netherlands (NL)

How to cite

APA:

Schmidt, S., Luecken, M.D., Truembach, D., Hembach, S., Niedermeier, K.M., Wenck, N.,... Wurst, W. (2022). Primary cilia and SHH signaling impairments in human and mouse models of Parkinson's disease. Nature Communications, 13(1). https://doi.org/10.1038/s41467-022-32229-9

MLA:

Schmidt, Sebastian, et al. "Primary cilia and SHH signaling impairments in human and mouse models of Parkinson's disease." Nature Communications 13.1 (2022).

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