Plate IV.225 · Publications
Primary cilia and SHH signaling impairments in human and mouse models of Parkinson’s disease
Article in Nature Communications, 16 August 2022.
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.
Cite
@article{schmidt2022primary,
title = {{Primary cilia and SHH signaling impairments in human and mouse models of Parkinson’s disease}},
author = {Schmidt, Sebastian and Luecken, Malte D. and Trümbach, Dietrich and Hembach, Sina and Niedermeier, Kristina M. and Wenck, Nicole and Pflügler, Klaus and Stautner, Constantin and Böttcher, Anika and Lickert, Heiko and Ramirez-Suastegui, Ciro and Ahmad, Ruhel and Ziller, Michael J. and Fitzgerald, Julia C. and Ruf, Viktoria and van de Berg, Wilma D. J. and Jonker, Allert J. and Gasser, Thomas and Winner, Beate and Winkler, Jürgen and Vogt Weisenhorn, Daniela M. and Giesert, Florian and Theis, Fabian J. and Wurst, Wolfgang},
journal = {Nature Communications},
publisher = {Springer Science and Business Media LLC},
year = {2022},
month = aug,
doi = {10.1038/s41467-022-32229-9},
url = {https://doi.org/10.1038/s41467-022-32229-9},
pmid = {35974013},
pmcid = {PMC9380673}
}