G-Quadruplexes as pathogenic drivers in neurodegenerative disorders

Wang, Ernest; Thombre, Ravi; Shah, Yajas; Latanich, Rachel; Wang, Jiou

doi:10.1093/nar/gkab164

Cited by 91 publications

(75 citation statements)

References 138 publications

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“…Other cell-based studies demonstrate the presence of nuclear G4 structures [ 63 , 64 ]. Collectively, the above studies suggest an important role for G-flipons in localizing cellular machines to regions where outcomes modify both normal function and disease risk [ 65 ].…”

Section: G-fliponsmentioning

confidence: 99%

The Simple Biology of Flipons and Condensates Enhances the Evolution of Complexity

Herbert

2021

Molecules

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The classical genetic code maps nucleotide triplets to amino acids. The associated sequence composition is complex, representing many elaborations during evolution of form and function. Other genomic elements code for the expression and processing of RNA transcripts. However, over 50% of the human genome consists of widely dispersed repetitive sequences. Among these are simple sequence repeats (SSRs), representing a class of flipons, that under physiological conditions, form alternative nucleic acid conformations such as Z-DNA, G4 quartets, I-motifs, and triplexes. Proteins that bind in a structure-specific manner enable the seeding of condensates with the potential to regulate a wide range of biological processes. SSRs also encode the low complexity peptide repeats to patch condensates together, increasing the number of combinations possible. In situations where SSRs are transcribed, SSR-specific, single-stranded binding proteins may further impact condensate formation. Jointly, flipons and patches speed evolution by enhancing the functionality of condensates. Here, the focus is on the selection of SSR flipons and peptide patches that solve for survival under a wide range of environmental contexts, generating complexity with simple parts.

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Section: G-fliponsmentioning

confidence: 99%

The Simple Biology of Flipons and Condensates Enhances the Evolution of Complexity

Herbert

2021

Molecules

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“…It is also well documented that AU-rich elements in the 3' UTRs can destabilize mRNA [78]. What may be of particular concern is the fact that GC enrichment content in vaccine mRNAs results in an enhanced ability for potential G quadruplex (pG4) formations in these structures, and this could cause onset of neurological disease [79]. Remarkably, the human prion protein (PrP) genetic sequence contains multiple G4 forming motifs, and their presence may form the missing link in the initial conversion of PrP to the misfolded form, PrPsc [80].…”

Section: Gc Enrichment and Potential G4 (Pg4) Structures In Vaccine Mrnasmentioning

confidence: 99%

Innate Immune Suppression by SARS-CoV-2 mRNA Vaccinations: The role of G-quadruplexes, exosomes and microRNAs

Seneff

Nigh

Kyriakopoulos³

et al. 2022

Preprint

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The mRNA SARS-CoV-2 vaccines were brought to market in response to the widely perceived public health crises of Covid-19. The utilization of mRNA vaccines in the context of infectious disease had no precedent, but desperate times seemed to call for desperate measures. The mRNA vaccines utilize genetically modified mRNA encoding spike proteins. These alterations hide the mRNA from cellular defenses, promote a longer biological half-life for the proteins, and provoke higher overall spike protein production. However, both experimental and observational evidence reveals a very different immune response to the vaccines compared to the response to infection with SARS-CoV-2. As we will show, the genetic modifications introduced by the vaccine are likely the source of these differential responses. In this paper, we present the evidence that vaccination, unlike natural infection, induces a profound impairment in type I interferon signaling, which has diverse adverse consequences to human health. We explain the mechanism by which immune cells release into the circulation large quantities of exosomes containing spike protein along with critical microRNAs that induce a signaling response in recipient cells at distant sites. We also identify potential profound disturbances in regulatory control of protein synthesis and cancer surveillance. These disturbances are shown to have a potentially direct causal link to neurodegenerative disease, myocarditis, immune thrombocytopenia, Bell’s palsy, liver disease, impaired adaptive immunity, increased tumorigenesis, and DNA damage. We show evidence from adverse event reports in the VAERS database supporting our hypothesis. We believe a comprehensive risk/benefit assessment of the mRNA vaccines excludes them as positive contributors to public health, even in the context of the Covid-19 pandemic.

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“… 34 , 35 However, accumulating evidence suggests important functional roles for G4 in neurological and viral diseases. 36 , 37 In the development and homeostasis of normal tissue, G4s have been implicated in more RNA-related mechanisms, such as mRNA splicing and localization, even regulating noncoding RNAs. Beyond different G4-related pathogenetic mechanisms of these diseases, the emerging role of G4s as therapeutic intervention of neurological disorder and antiviral is less explored.…”

Section: Functions Of the G-quadruplex In Vivomentioning

confidence: 99%

G-Quadruplexes in Neurobiology and Virology: Functional Roles and Potential Therapeutic Approaches

Huang

Zhou

2021

JACS Au

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A G-quadruplex (G4) is a four-stranded nucleic acid secondary structure maintained by Hoogsteen hydrogen bonds established between four guanines. Experimental studies and bioinformatics predictions support the hypothesis that these structures are involved in different cellular functions associated with both DNA and RNA processes. An increasing number of diseases have been shown to be associated with abnormal G4 regulation. Here, we describe the existence of G4 and then discuss G4-related pathogenic mechanisms in neurodegenerative diseases and the viral life cycle. Furthermore, we focus on the role of G4s in the design of antiviral therapy and neuropharmacology, including G4 ligands, G4-based aptamers, G4-related proteins, and CRISPR-based sequence editing, along with a discussion of limitations and insights into the prospects of this unusual nucleic acid secondary structure in therapeutics. Finally, we highlight progress and challenges in this field and the potential G4-related research fields.

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G-Quadruplexes as pathogenic drivers in neurodegenerative disorders

Cited by 91 publications

References 138 publications

The Simple Biology of Flipons and Condensates Enhances the Evolution of Complexity

The Simple Biology of Flipons and Condensates Enhances the Evolution of Complexity

Innate Immune Suppression by SARS-CoV-2 mRNA Vaccinations: The role of G-quadruplexes, exosomes and microRNAs

G-Quadruplexes in Neurobiology and Virology: Functional Roles and Potential Therapeutic Approaches

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