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, Jürgen
AU - Vogt Weisenhorn, Daniela M.
AU - Giesert, Florian
AU - Theis, Fabian J.
AU - Wurst, Wolfgang
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
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 - 10.1038/s41467-022-32229-9
DO - 10.1038/s41467-022-32229-9
M3 - Article
C2 - 35974013
AN - SCOPUS:85135989400
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4819
ER -