Actin Remodeling: Bridging the Gap Between Mistranslation and Dedifferentiation
Unraveling Phase II of Spike Protein Endothelial Disease (SPED): Spike Protein Progeria Syndrome (SPPS)
S1-RBD engagement initiates focal adhesion formation and actin organization. FN-null MEFs (2.5 × 103 cells/cm2) were seeded on coverslips coated with 500 nM S1-RBD (left) or FNIII10 (right). Cells were incubated for 4 h prior to fixation and immunofluorescent staining for vinculin (green), actin (TRITC-phalloidin, white), or phosphotyrosine (4G10, red). Arrowheads represent colocalization of vinculin and phosphotyrosine within focal adhesions (closed) and engagement with the actin cytoskeleton (open). Representative images shown from one of four independent experiments. The scale bar represents 10 μm.
It has been determined that the Spike Protein of SARS-CoV-2 has the ability to remodel the actin cytoskeleton. The image above demonstrates how it induces this remodeling.
S1-RBD triggered tyrosine phosphorylation of paxillin, a central adaptor protein whose SH2 domains require phosphorylation at residues Y118 and Y31 for activation and cytoskeletal remodeling.
Receptor-binding domain of SARS-CoV-2 is a functional αv-integrin agonist
Also, this same remodeling has been proven to occur in platelets.
We hypothesized that the binding of the SARS-CoV-2 is mediated by integrin receptors based on the following reasons; (1) the activation of platelets is governed by filopodia formation, (2) filopodia formation is initiated by integrin receptors, (3) the major receptors on the platelets are integrin receptors and (4) SARS-CoV-2 S protein contains a RGD sequence in the RBD, which is recognized by a subtype of integrin, and therefore we tested the interaction of platelet-expressed integrins with S protein.
Direct Cryo-ET observation of platelet deformation induced by SARS-CoV-2 spike protein
I believe this apparent ubiquitous ability of the Spike Protein to remodel the cytoskeleton may be one of the missing links in understanding the pathogenesis of the Spike Protein. If we examine the cytoskeleton and disease, we observe the entire panoply of conditions that can arise post COVID infection and Spike Protein exposure. This may also explain why the presentation is so heterogeneous. And why it is so unique to each individual.
Let us look at actin remodeling in relation to common Long COVID (PASC) symptoms.
Clarkson et al review the crucial role of actin cytoskeletal abnormalities in the development of congenital myopathy. Congenital myopathies constitute a heterogeneous group of disorders characterized by skeletal muscle weakness. Three major forms have been identified: actin myopathy, intra-nuclear rod myopathy, and nemaline myopathy. So far, five genes have been linked to congenital myopathy including α-actin, α- and β-tropomyosin, troponin-T, and nebulin; all are components of the thin filament of the sarcomere.
Astocytes are the most abundant cells in the mammalian central nervous system (CNS), yet knowledge about their function in health and disease is limited. Recent experimental data in mice show that when astrocyte intermediate filaments are ablated, reactive gliosis in various CNS diseases is altered and the signs of CNS degeneration become more prominent. Dominant mutations in the GFAP gene have been shown to lead to Alexander disease, a fatal neurodegenerative condition in humans. This is further elaborated in the paper by Cairns et al, which focuses on the cytoskeleton in neurodegenerative diseases. The discovery of mutations in neuronal intermediate filament and tau genes had firmly established the importance of neuronal intermediate filament proteins and tau in the pathogenesis of neurodegenerative disease. Intermediate filament gene mutations cause Charcot–Marie–Tooth disease and amyotropic lateral sclerosis. Tau gene mutations are responsible for fronto-temporal dementia with parkinsonism and tau polymorphisms are risk factors for progressive supranuclear palsy and corticobasilar degeneration. In vitro studies and transgenic animal models are presently being exploited to elucidate genotype–phenotype correlations and the details of cytoskeletal protein functions in cells of the nervous system.
Calle et al review the adhesive and motile behaviour of dendritic cells and the role of their cytoskeleton in cell adhesion and migration. As migration and cell–cell adhesion constitute essential elements in the development of an acquired immune response, disturbances of dendritic cell motility and adhesion have serious effects on the function of the immune system. This is the case in patients with the Wiskott–Aldrich syndrome (WAS), a syndrome characterized by immune dysregulation and microthrombocytopenia, and which lack the Wiskott–Aldrich syndrome protein (WASP).
Because of its intimate interaction with the cytoskeleton, Broers et al review the role that the nuclear lamina plays in the cell nucleus and in cell structure. Nuclear lamins form a fibrous nucleoskeletal network of intermediate-sized filaments that underlies the inner nuclear membrane, and have profound influences on nuclear structure and function, as they are building blocks on the one hand, and transcription regulators on the other. Which of these identities underlies the laminopathies, a spectrum of genetic diseases caused by mutations in lamins or lamin-associated proteins, is still a matter of speculation, but recent studies have shed more light on the cell biological basis of these pathologies.
The cytoskeleton and disease
I recommend all to read the excellent article cited above.
It should be noted that Hutchinson-Gilford (“THE” Progeria Disease) is a laminopathy.
Looking at how the Spike Protein induces actin remodeling can help us explain the diverse pathologies which may emerge in Long COVID and after Spike Protein exposure.
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I reached the same conclusion as you Walter. Cytoskeleton disruption inhibits neurotransmission in LC without killing the neurone.
Pathophysiology of "brain fog"
Thank you Walter ... as I read this I think about all the abruptions and premature births ... poor placentas 🥲... ugggh . Think about these athletes hearts and dropping dead , didn’t have a chance. Damar Hamlin is a very blessed young man . The examples are endless!! You a real gem Walter . 🤗