Aptamers targeting amyloidogenic proteins and their emerging role in neurodegenerative diseases

Murakami, Kazuma; Izuo, Naotaka; Bitan, Gal

doi:10.1016/j.jbc.2021.101478

Cited by 22 publications

(16 citation statements)

References 165 publications

(235 reference statements)

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“…Intriguingly, a number of artificial nucleic acid molecules, RNA and DNA aptamers, have been designed to impact protein aggregation 4,70 . For instance, an aptamer called T-SO517, developed by Ikebukuro and colleagues against oligomeric αS140, bound not only to the target but also to Aβ40 oligomers 71 .…”

Section: Discussionmentioning

confidence: 99%

A Computational Approach Reveals the Ability of Amyloids to Sequester RNA: the Alpha Synuclein Case

Rupert

Monti

Zacco

et al. 2022

Preprint

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The modulating effect of nucleic acids on protein aggregation has recently come into the spotlight, with RNA shown to either prevent or promote protein assembly depending on the molecular context. Here, we computed the biophysical properties of amyloids and observed a trend indicating that regions outside the aggregates core are highly prone to interact with nucleic acids. In the case of alpha synuclein (aS), an intrinsically disordered protein abundantly expressed in the brain, found in the nucleus and involved in Parkinson's disease, our predictions indicate that regions outside the aggregate are able to contact RNA, but the acidic C-terminal prevents the formation of stable interactions. We performed aggregation assays with both the wild type alpha-synuclein (aS140) as well as a C-terminally truncated isoform (aS103) and found that while RNA increases the aggregation rate of aS103, it decreases that of aS140, although at higher RNA concentrations the trend is inverted. To further elucidate the effects driving this behavior, we built a general dynamic model that describes the aggregation process of monomers in the presence of RNA. Our predictions indicate that RNA affects aS103 and aS140 aggregation in a non-linear manner and prioritize the interaction between RNA and aggregate as the most relevant. To confirm this, we extracted RNA from aS103 and aS140 aggregates and observed that they indeed acquire distinct RNA-sequestering abilities. Our research demonstrates that binding to transcripts can drastically alter the aggregation of a protein and represents an important gain-of-function mechanism to be further investigated.

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Section: Discussionmentioning

confidence: 99%

A Computational Approach Reveals the Ability of Amyloids to Sequester RNA: the Alpha Synuclein Case

Rupert

Monti

Zacco

et al. 2022

Preprint

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“…Aptamers extracted by affinity screening from the oligonucleotide library containing 10 14 –10 15 random sequences by in vitro SELEX technology can theoretically bind an unlimited range of targets, including proteins associated with cancer, cardiovascular disease, neurodegenerative diseases, , and inflammation, among many others. Most TPD technologies cannot degrade cell membrane proteins, but numerous aptamers can bind them with high specificity and affinity. , These aptamers are expected to provide more possibilities for membrane protein degradation.…”

Section: Aptamers: Another Opportunity For Tpd Technologymentioning

confidence: 99%

Aptamer-Based Targeted Protein Degradation

et al. 2023

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The selective removal of misfolded, aggregated, or aberrantly overexpressed protein plays an essential role in maintaining protein-dominated biological processes. In parallel, the precise knockout of abnormal proteins is inseparable from the accurate identification of proteins within complex environments. Guided by these precepts, small molecules, or antibodies, are commonly used as protein recognition tools for developing targeted protein degradation (TPD) technology. Indeed, TPD has shown tremendous prospects in chronic diseases, rare diseases, cancer research, and other fields. Meanwhile, aptamers are short RNA or DNA oligonucleotides that can bind to target proteins with high specificity and strong affinity. Accordingly, aptamers are actively used in designing and constructing TPD technology. In this perspective, we provide a brief introduction to TPD technology in its current progress, and we summarize its application challenges. Recent advances in aptamer-based TPD technology are reviewed, together with corresponding challenges and outlooks.

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“…Finally, the antagonistic function of nucleic acid medicine targeting nucleic acids, which can participate in the formation of amyloid coaggregates, is a promising lead in neurodegeneration therapeutics. 9 Nucleic acid aptamers are potential candidates, especially in the antiamyloid field, and various aptamers against amyloidogenic proteins, including oligomeric assembly, have been developed. We expect that these aptamers will suppress the interactions of amyloid coaggregates and further aggregation by shifting equilibrium to the disaggregated state.…”

Section: Perspectivesmentioning

confidence: 99%

“…In relation to amyloid assembly, "oligomer" is an ambiguously defined term used to describe dimers as well as hundreds of monomers when they are water soluble, which further complicates drug targeting. [7][8][9] Despite, over recent decades, substantial research effort directed at therapeutic interventions, there is no cure for oligomeric assembly as a therapy for neurodegeneration, which has two possible explanations as follows. 1 Reversible equilibrium: the formation of toxic oligomers resistant to degradation occurs, whereas the self-assembly process redirects toward dissociation back to nontoxic monomers.…”

Section: Introductionmentioning

confidence: 99%

Interactions of amyloid coaggregates with biomolecules and its relevance to neurodegeneration

Murakami

Ono

2022

The FASEB Journal

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The aggregation of amyloidogenic proteins is a pathological hallmark of various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In these diseases, oligomeric intermediates or toxic aggregates of amyloids cause neuronal damage and degeneration. Despite the substantial effort made over recent decades to implement therapeutic interventions, these neurodegenerative diseases are not yet understood at the molecular level. In many cases, multiple disease-causing amyloids overlap in a sole pathological feature or a sole disease-causing amyloid represents multiple pathological features. Various amyloid pathologies can coexist in the same brain with or without clinical presentation and may even occur in individuals without disease.From sparse data, speculation has arisen regarding the coaggregation of amyloids with disparate amyloid species and other biomolecules, which are the same characteristics that make diagnostics and drug development challenging. However, advances in research related to biomolecular condensates and structural analysis have been used to overcome some of these challenges. Considering the development of these resources and techniques, herein we review the cross-seeding of amyloidosis, for example, involving the amyloids amyloid β, tau, αsynuclein, and human islet amyloid polypeptide, and their cross-inhibition by transthyretin and BRICHOS. The interplay of nucleic acid-binding proteins, such as prions, TAR DNA-binding protein 43, fused in sarcoma/translated in liposarcoma, and fragile X mental retardation polyglycine, with nucleic acids in the pathology of neurodegeneration are also described, and we thereby highlight the potential clinical applications in central nervous system therapy.How to cite this article: Murakami K, Ono K. Interactions of amyloid coaggregates with biomolecules and its relevance to neurodegeneration.

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Aptamers targeting amyloidogenic proteins and their emerging role in neurodegenerative diseases

Cited by 22 publications

References 165 publications

A Computational Approach Reveals the Ability of Amyloids to Sequester RNA: the Alpha Synuclein Case

A Computational Approach Reveals the Ability of Amyloids to Sequester RNA: the Alpha Synuclein Case

Aptamer-Based Targeted Protein Degradation

Interactions of amyloid coaggregates with biomolecules and its relevance to neurodegeneration

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