Identification of Tau Stem Loop RNA Stabilizers

Donahue, Christine P.; Ni, Jake; Rozners, Eriks; Glicksman, Marcie A.; Wolfe, Michael S.

doi:10.1177/1087057107302676

Cited by 35 publications

(36 citation statements)

References 35 publications

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“…Stabilization of the RNA’s structure restores normal splicing patterns (Donahue et al, 2006) (Figure 7). A high throughput, FRET-based screen identified that the intercalator mitoxantrone (MTX, LDN-13978) stabilizes the mutated MAPT hairpin (Donahue et al, 2007). Importantly, mere intercalating ability is not sufficient for stabilization (Donahue et al, 2007).…”

Section: Leveraging Rna Structure To Design Chemical Probes Of Functionmentioning

confidence: 99%

“…A high throughput, FRET-based screen identified that the intercalator mitoxantrone (MTX, LDN-13978) stabilizes the mutated MAPT hairpin (Donahue et al, 2007). Importantly, mere intercalating ability is not sufficient for stabilization (Donahue et al, 2007). A structural study of MTX complexed with the MAPT hairpin by NMR spectroscopy revealed that MTX binds the bulge region of the stem-loop (Zheng et al, 2009).…”

Section: Leveraging Rna Structure To Design Chemical Probes Of Functionmentioning

confidence: 99%

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RNA Structures as Mediators of Neurological Diseases and as Drug Targets

Bernat

Disney

2015

Neuron

115

107

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RNAs adopt diverse folded structures that are essential for function and thus play critical roles in cellular biology. A striking example of this is the ribosome, a complex, three-dimensionally folded macromolecular machine that orchestrates protein synthesis. Advances in RNA biochemistry, structural and molecular biology, and bioinformatics have revealed other non-coding RNAs whose functions are dictated by their structure. It is not surprising that aberrantly folded RNA structures contribute to disease. In this review, we provide a brief introduction into RNA structural biology and then describe how RNA structures function in cells and cause or contribute to neurological disease. Finally, we highlight successful applications of rational design principles to provide chemical probes and lead compounds targeting structured RNAs. Based on several examples of well-characterized RNA-driven neurological disorders, we demonstrate how designed small molecules can facilitate study of RNA dysfunction, elucidating previously unknown roles for RNA in disease, and provide lead therapeutics.

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Section: Leveraging Rna Structure To Design Chemical Probes Of Functionmentioning

confidence: 99%

Section: Leveraging Rna Structure To Design Chemical Probes Of Functionmentioning

confidence: 99%

RNA Structures as Mediators of Neurological Diseases and as Drug Targets

Bernat

Disney

2015

Neuron

115

107

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“…Having validated the tau stem-loop RNA as a significant regulatory element in controlling tau mRNA splicing, we designed a high-throughput screen to identify small molecule ligands of the stem-loop RNA and developed other assays to validate the results of this screen [38]. Such compounds should stabilize the stem-loop and lower the 4R-to-3R ratio (i.e., do the opposite of disease-causing mutations).…”

Section: Tau Mrnamentioning

confidence: 99%

Targeting mRNA for Alzheimer’s and Related Dementias

Wolfe

2014

Scientifica

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Brain deposition of the amyloid beta-protein (Aβ) and tau are characteristic features in Alzheimer's disease (AD). Mutations in the Aβ precursor protein (APP) and a protease involved in Aβ production from APP strongly argue for a pathogenic role of Aβ in AD, while mutations in tau are associated with related disorders collectively called frontotemporal lobar degeneration (FTLD). Despite intense effort, therapeutic strategies that target Aβ or tau have not yet yielded medications, suggesting that alternative approaches should be pursued. In recent years, our laboratory has studied the role of mRNA in AD and FTLD, specifically those encoding tau and the Aβ-producing protease BACE1. As many FTLD-causing tau mutations destabilize a hairpin structure that regulates RNA splicing, we have targeted this structure with small molecules, antisense oligonucleotides, and small molecule-antisense conjugates. We have also discovered that microRNA interaction with the 3′-untranslated region of tau regulates tau expression. Regarding BACE1, we found that alternative splicing leads to inactive splice isoforms and antisense oligonucleotides shift splicing toward these inactive isoforms to decrease Aβ production. In addition, a G-quadruplex structure in the BACE1 mRNA plays a role in splice regulation. The prospects for targeting tau and BACE1 mRNAs as therapeutic strategies will be discussed.

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“…We previously reported a high-throughput screen to identify small, organic molecules that bind and stabilize the tau RNA hairpin and discovered mitoxantrone (MTX) as such a ligand [15]. Elucidation of the structure of MTX bound to the tau RNA hairpin by NMR revealed that the anthracene-dione ring system intercalates between two G–C base pairs, adjacent to an unpaired adenosine and close to the base of the hairpin (Fig.…”

Section: Introductionmentioning

confidence: 99%

Template-directed synthesis of a small molecule-antisense conjugate targeting an mRNA structure

Liu

Rodriguez

Wolfe

2014

Bioorganic Chemistry

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The targeting of structural features in mRNA with specificity remains a great chemical challenge. A hairpin structure near exon 10 in the pre-mRNA encoding the tau protein controls its splicing, and dementia-causing mutations that disrupt this structure increase exon 10 splicing. We previously reported the discovery of small molecules, mitoxantrone (MTX) and analogs, which bind to the tau RNA hairpin structure and the design of bipartite antisense oligonucleotides (ASOs) that simultaneously bind to the discontinuous sequences that flank this hairpin. Herein we report the synthesis of a bipartite ASO conjugated to MTX using the tau RNA hairpin and flanking sequences as a template. A set of six MTX analogs, each containing a linker-azide, and a set of ten bipartite ASOs, each containing a branched linker-alkyne, were synthesized and tested in combinatorial fashion for their ability to conjugate in the presence or absence of template RNA. A single template-dependent MTX–ASO conjugate was identified from among the 60 reaction mixtures, demonstrating that the MTX and ASO precursors could simultaneously bind the RNA template and allow proper positioning of azide and alkyne for 1,3-cycloaddition. While the MTX–ASO conjugate proved too cytotoxic for cell-based assays, the conjugate inhibited tau exon 10 splicing under cell-free conditions more effectively than MTX or bipartite ASO alone.

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Identification of Tau Stem Loop RNA Stabilizers

Cited by 35 publications

References 35 publications

RNA Structures as Mediators of Neurological Diseases and as Drug Targets

RNA Structures as Mediators of Neurological Diseases and as Drug Targets

Targeting mRNA for Alzheimer’s and Related Dementias

Template-directed synthesis of a small molecule-antisense conjugate targeting an mRNA structure

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