RhoA/ROCK Regulates Prion Pathogenesis by Controlling Connexin 43 Activity

Kim, Hee‐Jun; Kim, Mo‐Jong; Mostafa, Mohd Najib; Park, Jeong-Ho; Choi, Hongseok; Kim, Yong‐Sun; Choi, Eun‐Kyoung

doi:10.3390/ijms21041255

Cited by 22 publications

(22 citation statements)

References 64 publications

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“…It has been suggested that GJIC is reduced via RhoA-mediated Cx43 phosphorylation and Cx43/ZO-1/drebrin complex instability-mediated Cx43 degradation [ 97 ]. Curiously, in prion-infected neurons, RhoA seems to interact with Cx43, with RhoA/ROCK inhibition blocking Cx43 hemichannel activity [ 98 ]. In agreement with this hypothesis, previous work strongly suggested that RhoA activation is a key player in thrombin-induced inhibition of Cx43 hemichannel activity [ 74 ].…”

Section: Discussionmentioning

confidence: 99%

Cx43 and Associated Cell Signaling Pathways Regulate Tunneling Nanotubes in Breast Cancer Cells

Tishchenko

Azorín

Vidal-Brime

et al. 2020

Cancers

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Connexin 43 (Cx43) forms gap junctions that mediate the direct intercellular diffusion of ions and small molecules between adjacent cells. Cx43 displays both pro- and anti-tumorigenic properties, but the mechanisms underlying these characteristics are not fully understood. Tunneling nanotubes (TNTs) are long and thin membrane projections that connect cells, facilitating the exchange of not only small molecules, but also larger proteins, organelles, bacteria, and viruses. Typically, TNTs exhibit increased formation under conditions of cellular stress and are more prominent in cancer cells, where they are generally thought to be pro-metastatic and to provide growth and survival advantages. Cx43 has been described in TNTs, where it is thought to regulate small molecule diffusion through gap junctions. Here, we developed a high-fidelity CRISPR/Cas9 system to knockout (KO) Cx43. We found that the loss of Cx43 expression was associated with significantly reduced TNT length and number in breast cancer cell lines. Notably, secreted factors present in conditioned medium stimulated TNTs more potently when derived from Cx43-expressing cells than from KO cells. Moreover, TNT formation was significantly induced by the inhibition of several key cancer signaling pathways that both regulate Cx43 and are regulated by Cx43, including RhoA kinase (ROCK), protein kinase A (PKA), focal adhesion kinase (FAK), and p38. Intriguingly, the drug-induced stimulation of TNTs was more potent in Cx43 KO cells than in wild-type (WT) cells. In conclusion, this work describes a novel non-canonical role for Cx43 in regulating TNTs, identifies key cancer signaling pathways that regulate TNTs in this setting, and provides mechanistic insight into a pro-tumorigenic role of Cx43 in cancer.

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Section: Discussionmentioning

confidence: 99%

Cx43 and Associated Cell Signaling Pathways Regulate Tunneling Nanotubes in Breast Cancer Cells

Tishchenko

Azorín

Vidal-Brime

et al. 2020

Cancers

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“…From a molecular point of view, the overactivation of ROCKs in neuronal stem cells and mature neurons infected with prions, affect the neuronal polarity and connectivity by altering the dynamics of both FAs and the actin cytoskeleton, the latter being necessary to sheath the axon and to stabilize the synaptic button (Figures 3A,B). Beyond in vitro neuronal cell models, ROCKs oversignaling was also evidenced in vivo in the brain of prion-infected mice according to cofilin overphosphorylation (Alleaume-Butaux et al, 2015;Kim et al, 2020) and was confirmed by a kinomics approach (Shott et al, 2014). In 2018, Zafar et al provided evidence for altered cofilin and deregulation of upstream regulators (ROCK-2, LIMK1) in the cortex and cerebellum of humans with sporadic Creutzfeldt-Jakob disease (Zafar et al, 2018).…”

Section: Prion Infection Rock Oversignaling and Polarity Alterationsmentioning

confidence: 95%

The Cellular Prion Protein—ROCK Connection: Contribution to Neuronal Homeostasis and Neurodegenerative Diseases

Schneider

Baudry

Pietri

et al. 2021

Front. Cell. Neurosci.

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Amyloid-based neurodegenerative diseases such as prion, Alzheimer's, and Parkinson's diseases have distinct etiologies and clinical manifestations, but they share common pathological events. These diseases are caused by abnormally folded proteins (pathogenic prions PrPSc in prion diseases, β-amyloids/Aβ and Tau in Alzheimer's disease, α-synuclein in Parkinson's disease) that display β-sheet-enriched structures, propagate and accumulate in the nervous central system, and trigger neuronal death. In prion diseases, PrPSc-induced corruption of the physiological functions exerted by normal cellular prion proteins (PrPC) present at the cell surface of neurons is at the root of neuronal death. For a decade, PrPC emerges as a common cell surface receptor for other amyloids such as Aβ and α-synuclein, which relays, at least in part, their toxicity. In lipid-rafts of the plasma membrane, PrPC exerts a signaling function and controls a set of effectors involved in neuronal homeostasis, among which are the RhoA-associated coiled-coil containing kinases (ROCKs). Here we review (i) how PrPC controls ROCKs, (ii) how PrPC-ROCK coupling contributes to neuronal homeostasis, and (iii) how the deregulation of the PrPC-ROCK connection in amyloid-based neurodegenerative diseases triggers a loss of neuronal polarity, affects neurotransmitter-associated functions, contributes to the endoplasmic reticulum stress cascade, renders diseased neurons highly sensitive to neuroinflammation, and amplifies the production of neurotoxic amyloids.

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“…RhoA, one family member of the Rho-GTPases, plays a key role in cell remodeling 20 through activation of ROCKs and its interactions with different connexins has been described in other cell types 21,22 . We thus tested the activation of RhoA by assessing levels of RhoA-GTP using immunohistochemistry, and found a strong increase in KD mice (Fig.…”

Section: Astroglial Cx30 Closes the Critical Period By Downregulatingmentioning

confidence: 99%

Astrocytes close the critical period for visual plasticity

Ribot

Breton

Calvo

et al. 2020

Preprint

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Brain postnatal development is characterized by critical periods of experience-dependent remodeling. Termination of these periods of intense plasticity is associated with settling of neuronal circuits, allowing for efficient information processing. Failure to end critical periods thus results in neurodevelopmental disorders. Yet, the cellular processes defining the timing of these developmental periods remain unclear. Here we show in the mouse visual cortex that astrocytes control the closure of the critical period. We uncover a novel underlying pathway involving regulation of the extracellular matrix that allows interneurons maturation via an unconventional astroglial connexin signaling. We find that timing of the critical period closure is controlled by a marked developmental upregulation of the astroglial protein connexin 30 that inhibits expression of the matrix degrading enzyme MMP9 through the RhoA-GTPase signaling pathway. Our results thus demonstrate that astrocytes not only influence activity and plasticity of single synapses, but are also key elements in the experience-dependent wiring of brain developing circuits. This work, by revealing that astrocytes promote the maturation of inhibitory circuits, hence provide a new cellular target to alleviate malfunctions associated to impaired closure of critical periods.

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RhoA/ROCK Regulates Prion Pathogenesis by Controlling Connexin 43 Activity

Cited by 22 publications

References 64 publications

Cx43 and Associated Cell Signaling Pathways Regulate Tunneling Nanotubes in Breast Cancer Cells

Cx43 and Associated Cell Signaling Pathways Regulate Tunneling Nanotubes in Breast Cancer Cells

The Cellular Prion Protein—ROCK Connection: Contribution to Neuronal Homeostasis and Neurodegenerative Diseases

Astrocytes close the critical period for visual plasticity

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