Ion-dependent Conformational Switching by a DNA Aptamer That Induces Remyelination in a Mouse Model of Multiple Sclerosis

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2012 Nov 24

PMID 23175609

Citations 12

Authors

John Smestad

L James Maher 3rd

Affiliations

Soon will be listed here.

Abstract

We recently reported that a guanosine-rich 40-mer DNA aptamer (LJM-3064) mediates remyelination in the Theiler's murine encephalomyelitis virus mouse model of multiple sclerosis. Here, we characterize the G-quadruplex forms of this aptamer in vitro, and demonstrate using circular dichroism spectroscopy that LJM-3064 undergoes a monovalent ion-dependent conformational switch. In the presence of sodium ions and no potassium ions, LJM-3064 adopts an antiparallel-stranded G-quadruplex structure. When presented with low concentrations of potassium ions in a buffer that mimics the composition of interstitial fluid and blood plasma, LJM-3064 rapidly switches to a parallel-stranded G-quadruplex conformation, which is presumably the physiologically active folded form. We characterize these conformational states using dimethyl sulfate reactivity studies and Bal 31 nuclease probing. Our analysis indicates that only the 5'-terminal 26 nucleotides are involved in G-quadruplex formation. Thermodynamic characterization of LJM-3064 at physiologically relevant ion concentrations reveals the G-quadruplex to be metastable at human body temperature. These data provide important structural and thermodynamic insights that may be valuable in optimizing LJM-3064 as a therapeutic remyelinating agent.

Citing Articles

DNA aptamers that modulate biological activity of model neurons.

Rolli J, Pearson K, Wilbanks B, Hrstka S, Minotti A, Studer L Mol Ther Nucleic Acids. 2024; 35(4):102392.

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Application of aptamers in regenerative medicine.

Luo Z, Chen S, Zhou J, Wang C, Li K, Liu J Front Bioeng Biotechnol. 2022; 10:976960.

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Nucleic Acids as Novel Therapeutic Modalities to Address Multiple Sclerosis Onset and Progression.

Baharlooi H, Mansourabadi A, Minbashi Moeini M, Mohamed Khosroshahi L, Azimi M Cell Mol Neurobiol. 2021; 42(8):2611-2627.

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Role of MicroRNAs, Aptamers in Neuroinflammation and Neurodegenerative Disorders.

Khan I, Preeti K, Fernandes V, Khatri D, Singh S Cell Mol Neurobiol. 2021; 42(7):2075-2095.

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G-Quadruplex-Forming Aptamers-Characteristics, Applications, and Perspectives.

Roxo C, Kotkowiak W, Pasternak A Molecules. 2019; 24(20).

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