Primary cilia and SHH signaling impairments in human and mouse models of Parkinson’s disease
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ABSTRACT:
PROVIDER: PRJNA735192 | ENA |
REPOSITORIES: ENA
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Project description: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 an increased SHH signal transduction. Inhibition of this pathway rescues the alterations in PC morphology and mitochondrial dysfunction. Thus, increased SHH activity due to ciliary dysfunction is needed for the development of pathoetiological phenotypes observed in sPD, like mitochondrial dysfunction. In sum, altered PC function is part of early PD pathoetiology and inhibiting the overactive SHH signaling is a potential neuroprotective therapy.
2022-06-23 | GSE176160 | GEO
Project description:BBS7 -SHH signaling activity regulates primary cilia for periodontal homeostasis
| PRJNA782351 | ENA
Project description:Background: Whereas cilia damage and reduced cilia beat frequency have been implicated as causative of reduced mucociliary clearance in smokers, theoretically mucociliary clearance could also be affected by cilia length. Based on models of mucociliary clearance predicting cilia length must exceed the 6 -7 μm airway surface fluid depth to generate force in the mucus layer, we hypothesized cilia height may be decreased in airway epithelium of normal smokers compared to nonsmokers. Methodology/Principal Findings: Cilia length in normal nonsmokers and smokers was evaluated in aldehyde-fixed, paraffin-embedded endobronchial biopsies, and air-dried and hydrated samples brushed from human airway epithelium via fiberoptic bronchoscopy. In 28 endobronchial biopsies, healthy smoker cilia length was reduced 15% compared to nonsmokers (p<0.05). In 47 air-dried samples of airway epithelial cells, smoker cilia length was reduced 13% compared to nonsmokers (p<0.0001). Analysis of the length of individual, detached cilia in 17 samples, smoker cilia length was reduced 9% compared to nonsmokers (p<0.05). Finally, in 16 fully hydrated, unfixed samples, smoker cilia length was reduced 7% compared to nonsmokers (p<0.05). Conclusions/significance: Models predict that a reduction in cilia length would reduce mucociliary clearance, suggesting that smoking-associated shorter airway epithelial cilia plays a significant role in the pathogenesis of smoking-induced lung disease.
2012-12-13 | E-GEOD-16696 | biostudies-arrayexpress
Project description:The primary cilium, a signaling organelle projecting from the surface of a cell, controls cellular physiology and behavior. The presence or absence of primary cilia is a distinctive feature of a given tumor type; however, whether and how the primary cilium contributes to tumorigenesis is unknown for most tumors. Medulloblastoma (MB) is a common pediatric brain cancer comprising four groups: SHH, WNT, group 3 (G3), and group 4 (G4). From 111 cases of MB, we show that primary cilia are abundant in SHH and WNT MBs but rare in G3 and G4 MBs. Using WNT and G3 MB mouse models, we show that primary cilia promote WNT MB by facilitating translation of mRNA encoding β-catenin, a major oncoprotein driving WNT MB, whereas cilium loss promotes G3 MB by disrupting cell cycle control and destabilizing the genome. Our findings reveal tumor type–specific ciliary functions and underlying molecular mechanisms. Moreover, we expand the function of primary cilia to translation control and reveal a molecular mechanism by which cilia regulate cell cycle progression, providing new frameworks for studying cilia function in normal and pathologic conditions.
2022-07-04 | GSE207008 | GEO
Project description: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.
| S-EPMC9380673 | biostudies-literature
Project description:Sporadic Parkinson’s Disease (sPD) is a progressive neurodegenerative disorder caused by a combination of genetic and environmental factors, however, the etiology remains largely elusive. Here, we used human iPSCs from late onset sPD patients, which were cultivated in vitro for up to 60 passages and screened for known PD associated alterations. Following long-term in vitro cultivation, exclusively neural cells derived from sPD patients developed a reduced mitochondrial respiration and glucose consumption reflecting a sPD specific state of hypometabolism. Integrated analysis of transcriptome, proteome and non-targeted metabolome data identified the citric acid cycle as being the bottleneck in sPD metabolism. A 13C metabolic flux analysis further unraveled the α-ketoglutarate dehydrogenase complex as being central for a reduced flux through the citric acid cycle. This resulted in a substrate availability problem for the electron transport chain and thus a reduced mitochondrial ATP production. Notably, this alterations in basal cellular metabolism were introduced by altered SHH signal transduction due to dysfunctional primary cilia. Upon inhibiting the enhanced SHH signal transduction in sPD, glucose uptake and the activity of the α-ketoglutarate dehydrogenase complex could be restored. Thus, inhibiting overactive SHH signaling maybe a potential neuroprotective therapy for sPD.
2023-10-05 | PXD038399 | Pride
Project description:Autophagy impairments in directly reprogrammed neurons in patients with idiopathic Parkinson’s disease
| PRJNA515626 | ENA
Project description:Development of the cerebellum requires precise regulation of granule neuron progenitor (GNP) proliferation. Although it is known that primary cilia are necessary to support GNP proliferation, the exact molecular mechanism governing primary cilia dynamics within GNPs remains elusive. Here, we establish the pivotal roles for the centrosomal kinase TTBK2 (Tau tubulin kinase-2) and the E3 ubiquitin ligase HUWE1 in GNP proliferation. We show that TTBK2 is highly expressed in proliferating GNPs under Sonic Hedgehog (SHH) signaling, coinciding with active GNP proliferation and the presence of primary cilia. TTBK2 stabilizes primary cilia by inhibiting their disassembly, thereby promoting GNP proliferation in response to SHH. Mechanistically, we identify HUWE1 as a novel centrosomal E3 ligase that facilitates primary cilia disassembly by targeting TTBK2 degradation. Disassembly of primary cilia serves as a trigger for GNP differentiation, allowing their migration from the external granule layer (EGL) of the cerebellum to the internal granule layer (IGL) for subsequent maturation. Moreover, we have established a link between TTBK2 and SHH-type medulloblastoma (SHH-MB), a tumor characterized by uncontrolled GNP proliferation. TTBK2 depletion inhibits SHH-MB proliferation, indicating that TTBK2 may be a potential therapeutic target for this cancer type. In summary, our findings reveal the mechanism governing cerebellar development and highlight a potential anti-cancer strategy for SHH-MB.
2024-06-03 | GSE268621 | GEO
Project description:Protein degradation impairment is strongly suspected to play a role in idiopathic Parkinson’s disease (PD). However, current tools and models are lacking to study such disease associated phenotypes across the PD patient population. Here, we generate functional induced dopaminergic neurons (iDANs) directly reprogrammed from adult dermal fibroblasts of patients with PD to investigate intra-neuronal autophagy alterations.
2019-06-01 | GSE125239 | GEO
Project description:Background: Whereas cilia damage and reduced cilia beat frequency have been implicated as causative of reduced mucociliary clearance in smokers, theoretically mucociliary clearance could also be affected by cilia length. Based on models of mucociliary clearance predicting cilia length must exceed the 6 -7 μm airway surface fluid depth to generate force in the mucus layer, we hypothesized cilia height may be decreased in airway epithelium of normal smokers compared to nonsmokers. Methodology/Principal Findings: Cilia length in normal nonsmokers and smokers was evaluated in aldehyde-fixed, paraffin-embedded endobronchial biopsies, and air-dried and hydrated samples brushed from human airway epithelium via fiberoptic bronchoscopy. In 28 endobronchial biopsies, healthy smoker cilia length was reduced 15% compared to nonsmokers (p<0.05). In 47 air-dried samples of airway epithelial cells, smoker cilia length was reduced 13% compared to nonsmokers (p<0.0001). Analysis of the length of individual, detached cilia in 17 samples, smoker cilia length was reduced 9% compared to nonsmokers (p<0.05). Finally, in 16 fully hydrated, unfixed samples, smoker cilia length was reduced 7% compared to nonsmokers (p<0.05).
2012-12-13 | GSE16696 | GEO