S100A6 is a positive regulator of PPP5C‐FKBP51‐dependent regulation of endothelial calcium signaling

Haldar, Barnita; Hamilton, Caleb; Solodushko, Viktoriya; Abney, Kevin A.; Alexeyev, Mikhail; Honkanen, Richard E.; Scammell, Jonathan G.; Cioffi, Donna L.

doi:10.1096/fj.201901777r

Cited by 14 publications

(5 citation statements)

References 59 publications

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“…Moreover, we have found interesting candidates in the HeLa proteome profiling that could explain or be related to the mentioned cellular disturbances (Figure 3C). S100A6, underexpressed, is a positive regulator of proliferation, migration and angiogenesis [60]- [62], and also a regulator of endothelial calcium signalling [63]. PKM, which was over-expressed in HeLa cells, is associated with apoptosis resistance [64].…”

Section: Discussionmentioning

confidence: 99%

Depletion of ALMS1 affects TGF-β signalling pathway and downstream processes such as cell migration and adhesion capacity

Bea-Mascato

Neira-Goyanes

Iglesias-Rodríguez

et al. 2021

Preprint

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Background: ALMS1 is a ubiquitous gene associated with Alström syndrome (ALMS). The main symptoms of ALMS affect multiple organs and tissues, generating at last, multi-organic fibrosis in the lungs, kidneys and liver. TGF-β is one of the main pathways implicated in fibrosis, controlling the cell cycle, apoptosis, cell migration, and epithelial-mesenchymal transition (EMT). Nevertheless, the role of ALMS1 gene in fibrosis generation and other implicated processes such as cell migration or epithelial-mesenchymal transition via the TGF-β pathway has not been elucidated yet. Methods: Initially, we evaluated how depletion of ALMS1 affects different processes like apoptosis, cell cycle and mitochondrial activity. Then, we performed proteomic profiling with TGF-β stimuli in HeLa ALMS1 -/- cells and validated the results by examining different EMT biomarkers using qPCR. The expression of these EMT biomarkers was validated in hTERT-BJ-5ta. Finally, we also evaluated the SMAD3 phosphorylation in BJ-5ta model and its cell migration capacity. Results: Depletion of ALMS1 generated apoptosis resistance to thapsigargin (THAP) and C2-Ceramide (C2-C), and G2/M cell cycle arrest in HeLa cells. For mitochondrial activity, results did not show significant differences between ALMS1 +/+ and ALMS1 -/-. Proteomic results showed inhibition of downstream pathways regulated by TGF-β. The protein-coding genes (PCG) were associated with processes like focal adhesion or cell-substrate adherens junction. EMT biomarkers VIM, DSP, and SNAI1 showed an opposite pattern to what would be expected when activating the EMT. Finally, inhibition of SNAI1 was consistent in BJ-5ta model, where a reduced activation of SMAD3 and a decrease in migratory capacity were also observed. Conclusion: ALMS1 has a role in controlling the cell cycle and the apoptosis processes. Moreover, the depletion of ALMS1 inhibits the signal transduction through the TGF-β/SMAD3/SNAI1, which could be affecting the cell migration capacity and EMT.

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Section: Discussionmentioning

confidence: 99%

Depletion of ALMS1 affects TGF-β signalling pathway and downstream processes such as cell migration and adhesion capacity

Bea-Mascato

Neira-Goyanes

Iglesias-Rodríguez

et al. 2021

Preprint

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“…Zinc can also bind tau directly to contribute to tau toxicity independent of tau hyperphosphorylation [134, 135]. S100A6 can also enhance the phosphatase activity of PPP5C towards p-tau [136]. Together, this data shows the novel astrocyte-oligodendrocyte hybrid cells overexpress neurotrophic factors in conjunction with suppression of EIF2-mediate stress response, suggesting a potential neuroprotective function or homeostatic role.…”

Section: Discussionmentioning

confidence: 99%

Single-cell transcriptomic and neuropathologic analysis reveals dysregulation of the integrated stress response in progressive supranuclear palsy

Whitney,

Song,

Sharma

et al. 2023

Preprint

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Progressive supranuclear palsy (PSP) is a sporadic neurodegenerative tauopathy variably affecting brainstem and cortical structures and characterized by tau inclusions in neurons and glia. The precise mechanism whereby these protein aggregates lead to cell death remains unclear. To investigate the contribution of these different cellular abnormalities to PSP pathogenesis, we performed single-nucleus RNA sequencing and analyzed 45,559 high quality nuclei targeting the subthalamic nucleus and adjacent structures from human post-mortem PSP brains with varying degrees of pathology compared to controls. Cell-type specific differential expression and pathway analysis identified both common and discrete changes in numerous pathways previously implicated in PSP and other neurodegenerative disorders. This included EIF2 signaling, an adaptive pathway activated in response to diverse stressors, which was the top activated pathway in vulnerable cell types. Using immunohistochemistry, we found that activated eIF2α was positively correlated with tau pathology burden in vulnerable brain regions. Multiplex immunofluorescence localized activated eIF2α positivity to hyperphosphorylated tau (p-tau) positive neurons and ALDH1L1-positive astrocytes, supporting the increased transcriptomic EIF2 activation observed in these vulnerable cell types. In conclusion, these data provide insights into cell-type-specific pathological changes in PSP and support the hypothesis that failure of adaptive stress pathways play a mechanistic role in the pathogenesis and progression of PSP.

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“…Zinc can also bind tau directly to contribute to tau toxicity independent of tau hyperphosphorylation 57, 58 . A recent report has revealed that S100A6 can also enhance the phosphatase activity of PPP5C towards p-tau 59 . This data further strengthens the idea that the hybrid subpopulation is associated with potential neuroprotective functions.…”

Section: Discussionmentioning

confidence: 99%

Single-cell atlas of progressive supranuclear palsy reveals a distinct hybrid glial cell population

Sharma

Song

Farrell

et al. 2021

Preprint

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Progressive supranuclear palsy (PSP) is a neurodegenerative disorder whose molecular complexity at a single cell level has not been evaluated. Here we analyzed 45,559 high quality nuclei from the subthalamic nucleus and associated basal ganglia regions from post-mortem human PSP brains with varying degrees of tau pathology compared to controls (n=3 per group). We identified novel astrocyte-oligodendrocyte hybrid cell populations that overexpress neurotropic factors in conjunction with suppression of the unfolded protein response pathway. Notably, trajectory analysis identified subpopulations of hybrid cells with distinct astrocytic, oligodendrocytic and hybrid molecular states that change from a neuroprotective hybrid cell to an astrocytic cell with impaired homeostatic function in PSP. Our single nucleus transcriptomic data provides insights into the cell-type-specific contributions to the disease for investigating the molecular and cellular basis of PSP

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S100A6 is a positive regulator of PPP5C‐FKBP51‐dependent regulation of endothelial calcium signaling

Cited by 14 publications

References 59 publications

Depletion of ALMS1 affects TGF-β signalling pathway and downstream processes such as cell migration and adhesion capacity

Depletion of ALMS1 affects TGF-β signalling pathway and downstream processes such as cell migration and adhesion capacity

Single-cell transcriptomic and neuropathologic analysis reveals dysregulation of the integrated stress response in progressive supranuclear palsy

Single-cell atlas of progressive supranuclear palsy reveals a distinct hybrid glial cell population

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