A transcriptional and post-transcriptional dysregulation of Dishevelled 1 and 2 underlies the Wnt signaling impairment in type I Gaucher disease experimental models

Costa, Roberto; Bellesso, Stefania; Lualdi, Susanna; Manzoli, Rosa; Pistorio, Valeria; Filocamo, Mirella; Moro, Enrico

doi:10.1093/hmg/ddz293

Cited by 4 publications

(4 citation statements)

References 35 publications

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“…The response to TNF also elicits cross-regulation with other important signaling pathways [ 66 ]. In the case of GD, NF-κB and Wnt signal dysregulation are of particular consequence for axonal guidance, lysosomal loss, and bone differentiation [ 67 , 68 , 69 ]. Our pathway analysis of C5a stimulation identified Wnt pathway genes, which are involved in development, arthritis, and cancer ( Supplemental Table S4 ).…”

Section: Resultsmentioning

confidence: 99%

C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages

Serfecz

Saadin

Santiago

et al. 2021

IJMS

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Gaucher disease (GD) is an autosomal recessive disorder caused by bi-allelic GBA1 mutations that reduce the activity of the lysosomal enzyme β-glucocerebrosidase (GCase). GCase catalyzes the conversion of glucosylceramide (GluCer), a ubiquitous glycosphingolipid, to glucose and ceramide. GCase deficiency causes the accumulation of GluCer and its metabolite glucosylsphingosine (GluSph) in a number of tissues and organs. In the immune system, GCase deficiency deregulates signal transduction events, resulting in an inflammatory environment. It is known that the complement system promotes inflammation, and complement inhibitors are currently being considered as a novel therapy for GD; however, the mechanism by which complement drives systemic macrophage-mediated inflammation remains incompletely understood. To help understand the mechanisms involved, we used human GD-induced pluripotent stem cell (iPSC)-derived macrophages. We found that GD macrophages exhibit exacerbated production of inflammatory cytokines via an innate immune response mediated by receptor 1 for complement component C5a (C5aR1). Quantitative RT-PCR and ELISA assays showed that in the presence of recombinant C5a (rC5a), GD macrophages secreted 8–10-fold higher levels of TNF-α compared to rC5a-stimulated control macrophages. PMX53, a C5aR1 blocker, reversed the enhanced GD macrophage TNF-α production, indicating that the observed effect was predominantly C5aR1-mediated. To further analyze the extent of changes induced by rC5a stimulation, we performed gene array analysis of the rC5a-treated macrophage transcriptomes. We found that rC5a-stimulated GD macrophages exhibit increased expression of genes involved in TNF-α inflammatory responses compared to rC5a-stimulated controls. Our results suggest that rC5a-induced inflammation in GD macrophages activates a unique immune response, supporting the potential use of inhibitors of the C5a-C5aR1 receptor axis to mitigate the chronic inflammatory abnormalities associated with GD.

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Section: Resultsmentioning

confidence: 99%

C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages

Serfecz

Saadin

Santiago

et al. 2021

IJMS

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“…The wide number of interactions of the Hippo pathway with many cellular mechanisms makes it a really promising target; it was indeed reported to be involved in the control of inflammation, ER stress, and cell death, all mechanisms altered in GD 43 , 70 , 71 . Moreover, it is known to directly interact with some specific pathways impaired in GD models, such as mTOR, Wnt/β-catenin, and cathepsins activity 15 , 72 , 73 . Therefore, understanding the pathological implications of Hippo in GD is particularly appealing also because many pharmacological modulators targeting Hippo are currently under evaluation for clinical applications.…”

Section: Discussionmentioning

confidence: 99%

Neuronopathic Gaucher disease models reveal defects in cell growth promoted by Hippo pathway activation

et al. 2023

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Gaucher Disease (GD), the most common lysosomal disorder, arises from mutations in the GBA1 gene and is characterized by a wide spectrum of phenotypes, ranging from mild hematological and visceral involvement to severe neurological disease. Neuronopathic patients display dramatic neuronal loss and increased neuroinflammation, whose molecular basis are still unclear. Using a combination of Drosophila dGBA1b loss-of-function models and GD patient-derived iPSCs differentiated towards neuronal precursors and mature neurons we showed that different GD- tissues and neuronal cells display an impairment of growth mechanisms with an increased cell death and reduced proliferation. These phenotypes are coupled with the downregulation of several Hippo transcriptional targets, mainly involved in cells and tissue growth, and YAP exclusion from nuclei. Interestingly, Hippo knock-down in the GBA-KO flies rescues the proliferative defect, suggesting that targeting the Hippo pathway can be a promising therapeutic approach to neuronopathic GD.

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“…Western blot. All procedures were performed as previously described 38 . Briefly, differentiated cells at day 5 were harvested and lysed in Tissue Extraction Reagent (ThermoFisher, Italy) in the presence of protease and phosphatase inhibitors (ThermoFisher, Italy).…”

Section: Generation Of Ids Mutant Luhmes Cellsmentioning

confidence: 99%

A novel CRISPR/Cas9-based iduronate-2-sulfatase (IDS) knockout human neuronal cell line reveals earliest pathological changes

Badenetti

Manzoli

Trevisan

et al. 2023

Sci Rep

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Multiple complex intracellular cascades contributing to Hunter syndrome (mucopolysaccharidosis type II) pathogenesis have been recognized and documented in the past years. However, the hierarchy of early cellular abnormalities leading to irreversible neuronal damage is far from being completely understood. To tackle this issue, we have generated two novel iduronate-2-sulfatase (IDS) loss of function human neuronal cell lines by means of genome editing. We show that both neuronal cell lines exhibit no enzymatic activity and increased GAG storage despite a completely different genotype. At a cellular level, they display reduced differentiation, significantly decreased LAMP1 and RAB7 protein levels, impaired lysosomal acidification and increased lipid storage. Moreover, one of the two clones is characterized by a marked decrease of the autophagic marker p62, while none of the two mutants exhibit marked oxidative stress and mitochondrial morphological changes. Based on our preliminary findings, we hypothesize that neuronal differentiation might be significantly affected by IDS functional impairment.

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A transcriptional and post-transcriptional dysregulation of Dishevelled 1 and 2 underlies the Wnt signaling impairment in type I Gaucher disease experimental models

Cited by 4 publications

References 35 publications

C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages

C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages

Neuronopathic Gaucher disease models reveal defects in cell growth promoted by Hippo pathway activation

A novel CRISPR/Cas9-based iduronate-2-sulfatase (IDS) knockout human neuronal cell line reveals earliest pathological changes

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