TY - JOUR
T1 - Primary cilia and SHH signaling impairments in human and mouse models of Parkinson’s disease
AU - Schmidt, Sebastian
AU - Luecken, Malte D.
AU - Trümbach, Dietrich
AU - Hembach, Sina
AU - Niedermeier, Kristina M.
AU - Wenck, Nicole
AU - Pflügler, Klaus
AU - Stautner, Constantin
AU - Böttcher, Anika
AU - Lickert, Heiko
AU - Ramirez-Suastegui, Ciro
AU - Ahmad, Ruhel
AU - Ziller, Michael J.
AU - Fitzgerald, Julia C.
AU - Ruf, Viktoria
AU - van de Berg, Wilma D. J.
AU - Jonker, Allert J.
AU - Gasser, Thomas
AU - Winner, Beate
AU - Winkler, J. rgen
AU - Vogt Weisenhorn, Daniela M.
AU - Giesert, Florian
AU - Theis, Fabian J.
AU - Wurst, Wolfgang
N1 - Funding Information: We thank Bernt Popp and André Reis (University Erlangen) for performing whole exome sequencing in hiPSCs; Markus J. Riemenschneider (University of Regensburg) for providing material; F. Marxreiter (University Erlangen) for providing clinical information; Michaela Farrell, Sonja Plötz, Annerose Kurz-Drexler, Tanja Orschmann, Susanne Badeke, Sebastian Lacher, Ipek Eroglu, Lisa Hornsteiner for excellent technical assistance; Alessandra Moretti (TUM) for discussions and comments; Volker Bergen (Helmholtz Zentrum München) for discussions about root cell analysis; Martin Jastroch (Stockholm University) for discussions about mitochondrial stress tests. Funding Information: This work was supported in part by the Bavarian Ministry of Science and the Arts in the framework of the ForIPS consortium (C.S., W.W., J.W., B.W.), the ForInter consortium (B.W., J.W., F.J.T.), the German Science Foundation Collaborative Research Center (CRC) 870 (to W.W. - K.M.N.), by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network MitoPD (Mitochondrial endophenotypes of Morbus Parkinson), under the auspices of the e:Med Programme (grant 031A430E to W.W. and 031A430A to T.G.), through the Joint Project HIT-Tau (High Throughput Approaches for the Individualized Therapy of Tau-Related Diseases – TP2: Grant 01EK1605C (to W.W. - D.T.), by the AMPro project - ‘Aging and Metabolic Programming’-, by the Incubator grant # ZT-I-0007 sparse2big (to F.J.T. – M.D.L.), by the Chan Zuckerberg Initiative DAF (advised fund of Silicon Valley Community Foundation, 182835) (to F.J.T. – M.D.L.), as well as by ‘ExNet-0041-Phase2-3 (SyNergy-HMGU)‘ through the Initiative and Network Fund of the Helmholtz Association (to H.L., F.G., M.D.L., F.J.T. and W.W.). Open Access funding enabled and organized by Projekt DEAL. Publisher Copyright: © 2022, The Author(s).
PY - 2022/12/1
Y1 - 2022/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85135989400&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-022-32229-9
DO - https://doi.org/10.1038/s41467-022-32229-9
M3 - Article
C2 - 35974013
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4819
ER -