Primary cilia and SHH signaling impairments in human and mouse models of Parkinson's disease
| Autor: | 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. van de Berg, Allert J. Jonker, Thomas Gasser, Beate Winner, Jürgen Winkler, Daniela M. Vogt Weisenhorn, Florian Giesert, Fabian J. Theis, Wolfgang Wurst |
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| Přispěvatelé: | Anatomy and neurosciences, Amsterdam Neuroscience - Neurodegeneration |
| Rok vydání: | 2021 |
| Předmět: |
Multidisciplinary
metabolism [Parkinson Disease] General Physics and Astronomy Parkinson Disease metabolism [Neural Stem Cells] General Chemistry Shh protein mouse genetics [Hedgehog Proteins] General Biochemistry Genetics and Molecular Biology Disease Models Animal Mice Neural Stem Cells genetics [Parkinson Disease] metabolism [Cilia] SHH protein human Animals Humans Hedgehog Proteins ddc:500 metabolism [Hedgehog Proteins] Cilia Signal Transduction |
| Zdroj: | Nature Communications, 13(1):4819. Nature Publishing Group UK Schmidt, S, Luecken, M D, Trümbach, D, Hembach, S, Niedermeier, K M, Wenck, N, Pflügler, K, Stautner, C, Böttcher, A, Lickert, H, Ramirez-Suastegui, C, Ahmad, R, Ziller, M J, Fitzgerald, J C, Ruf, V, van de Berg, W D J, Jonker, A J, Gasser, T, Winner, B, Winkler, J R, Vogt Weisenhorn, D M, Giesert, F, Theis, F J & Wurst, W 2022, ' Primary cilia and SHH signaling impairments in human and mouse models of Parkinson’s disease ', Nature Communications, vol. 13, no. 1, 4819 . https://doi.org/10.1038/s41467-022-32229-9 Nature Communications 13(1), 4819 (2022). doi:10.1038/s41467-022-32229-9 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-022-32229-9 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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