Prion Protein Endoproteolysis: Cleavage Sites, Mechanisms and Connections to Prion Disease DOI Creative Commons
Andrew R. Castle, David Westaway

Journal of Neurochemistry, Journal Year: 2025, Volume and Issue: 169(1)

Published: Jan. 1, 2025

ABSTRACT Highly abundant in neurons, the cellular prion protein (PrP C ) is an obligatory precursor to disease‐associated misfolded isoform denoted PrP Sc that accumulates rare neurodegenerative disorders referred either as transmissible spongiform encephalopathies (TSEs) or diseases. The ability of serve a substrate for this template‐mediated conversion process depends on several criteria but importantly includes presence absence certain endoproteolytic events performed at cell surface acidic endolysosomal compartments. major affecting are α‐ and β‐cleavages, review we outline sites within which cleavages occur, mechanisms potentially responsible their relevance pathology. Although association α‐cleavage with neuroprotection well‐supported, identify open questions regarding importance β‐cleavage TSEs suggest experimental approaches could provide clarification. We also combine findings from vitro cleavage assays mass spectrometry‐based studies fragments brain present updated view β‐cleavages may represent two distinct clusters proteolytic occur multiple neighbouring rather than single positions. Furthermore, highlight candidate best supported by literature; currently, despite proteases identified capable processing vitro, cell‐based models some cases, vivo, none have been shown conclusively cleave brain. Addressing knowledge gap will be crucial developing therapeutic interventions drive endoproteolysis neuroprotective direction. Finally, end briefly addressing other events, specifically ectodomain shedding, γ‐cleavage, generation atypical pathological familial disorder Gerstmann–Sträussler–Scheinker syndrome possibility additional form close N‐terminus. image

Language: Английский

Chemically Modified Platforms for Better RNA Therapeutics DOI

Yesi Shi,

Xueyan Zhen,

Yiming Zhang

et al.

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(3), P. 929 - 1033

Published: Jan. 29, 2024

RNA-based therapies have catalyzed a revolutionary transformation in the biomedical landscape, offering unprecedented potential disease prevention and treatment. However, despite their remarkable achievements, these encounter substantial challenges including low stability, susceptibility to degradation by nucleases, prominent negative charge, thereby hindering further development. Chemically modified platforms emerged as strategic innovation, focusing on precise alterations either RNA moieties or associated delivery vectors. This comprehensive review delves into platforms, underscoring significance augmenting performance translational prospects of therapeutics. It encompasses an in-depth analysis various chemically that been instrumental propelling therapeutics toward clinical utility. Moreover, scrutinizes rationale behind diverse chemical modification techniques aiming at optimizing therapeutic efficacy molecules, facilitating robust management. Recent empirical studies corroborating enhancement through modifications are highlighted. Conclusively, we offer profound insights transformative impact drugs delineates prospective trajectories for future development integration.

Language: Английский

Citations

44
The immunostimulatory nature of mRNA lipid nanoparticles DOI
Preeti Sharma,

Daniek Hoorn,

Anjaiah Aitha

et al.

Advanced Drug Delivery Reviews, Journal Year: 2024, Volume and Issue: 205, P. 115175 - 115175

Published: Jan. 11, 2024

Language: Английский

Citations

41
Transfer RNA modifications and cellular thermotolerance DOI Creative Commons
Takayuki Ohira, Tsutomu Suzuki

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(1), P. 94 - 106

Published: Jan. 1, 2024

Language: Английский

Citations

23
RNA dysregulation in neurodegenerative diseases DOI Creative Commons
Yini Li, Shuying Sun

The EMBO Journal, Journal Year: 2025, Volume and Issue: 44(3), P. 613 - 638

Published: Jan. 9, 2025

Dysregulation of RNA processing has in recent years emerged as a significant contributor to neurodegeneration. The diverse mechanisms and molecular functions underlying underscore the essential role regulation maintaining neuronal health function. molecules are bound by RNA-binding proteins (RBPs), interactions between RNAs RBPs commonly affected In this review, we highlight progress understanding dysregulated RNA-processing pathways causes RBP dysfunction across various neurodegenerative diseases. We discuss both established emerging RNA-mediated neuropathogenesis rapidly evolving field. Furthermore, explore development potential RNA-targeting therapeutic approaches for treatment

Language: Английский

Citations

3
Circular RNA vaccines with long-term lymph node-targeting delivery stability after lyophilization induce potent and persistent immune responses DOI Creative Commons
Jiawu Wan,

Zongmei Wang,

Lingli Wang

et al.

mBio, Journal Year: 2023, Volume and Issue: 15(1)

Published: Dec. 11, 2023

messenger RNA (mRNA) vaccines are a key technology in combating existing and emerging infectious diseases. However, the inherent instability of mRNA nonspecificity lipid nanoparticle-encapsulated (LNP) delivery systems result need for cold storage relatively short-duration immune response to vaccines. Herein, we develop novel vaccine form circRNAs encapsulated LNPs, circular structure enhances their stability. Lyophilization is considered most effective method long-term preservation this process may irreversible damage nanoparticles, particularly potential disruption targeting modifications on LNPs. During selection lymph node-targeting ligands, found that LNPs modified with mannose maintained physical properties almost unchanged after lyophilization. Additionally, specificity immunogenicity remained unaffected. In contrast, even addition cryoprotectants such as sucrose, were impaired, leading an obvious decrease immunogenicity. This be attributed protective role surface during Freshly prepared lyophilized mLNP-circRNA elicited comparable responses both rabies virus model SARS-CoV-2 model. Our data demonstrated elicit robust while improving stability lyophilization, no compromise tissue specificity. Therefore, mannose-modified LNP-circRNA represent promising design strategy.

Language: Английский

Citations

30
tRNA therapeutics for genetic diseases DOI
Jeff Coller, Zoya Ignatova

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 23(2), P. 108 - 125

Published: Dec. 4, 2023

Language: Английский

Citations

29
Natural antisense transcripts as versatile regulators of gene expression DOI
Andreas Werner, Aditi Kanhere, Claes Wahlestedt

et al.

Nature Reviews Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: April 17, 2024

Language: Английский

Citations

13
Biomarker potential of competing endogenous RNA networks in Polycystic Ovary Syndrome (PCOS) DOI Creative Commons
Roozbeh Heidarzadehpilehrood, Maryam Pirhoushiaran

Non-coding RNA Research, Journal Year: 2024, Volume and Issue: 9(2), P. 624 - 640

Published: Jan. 17, 2024

Polycystic ovary syndrome (PCOS) is the most common condition affecting women of reproductive age globally. PCOS continues to be largest contributing factor female infertility despite significant progress in our knowledge molecular underpinnings and treatment condition. The fact that a very diverse makes it one key reasons why we haven't been able overcome it. Non-coding RNAs (ncRNAs) are implicated development PCOS, according growing evidence. However, unclear how complex regulatory relationships between many ncRNA types contribute growth this malignancy. Competing endogenous RNA (ceRNA), recently identified mechanism world, suggests interactions various RNAs, including long non-coding (lncRNAs), microRNAs (miRNAs), transcribed pseudogenes, circular (circRNAs). Recent studies on have shown dysregulation multiple ceRNA networks (ceRNETs) these ncRNAs plays crucial roles developing defining characteristics development. And believed such finding may open new door for deeper comprehension PCOS's unexplored facets. In addition, provide fresh biomarkers effective therapy targets PCOS. This review will go over body information exists about primary ceRNETs before highlighting involvement several newly found number characteristics.

Language: Английский

Citations

12
RNA editing enzymes: structure, biological functions and applications DOI Creative Commons
Dejiu Zhang,

Lei Zhu,

Yanyan Gao

et al.

Cell & Bioscience, Journal Year: 2024, Volume and Issue: 14(1)

Published: March 16, 2024

Abstract With the advancement of sequencing technologies and bioinformatics, over than 170 different RNA modifications have been identified. However, only a few these can lead to base pair changes, which are called editing. editing is ubiquitous modification in mammalian transcriptomes an important co/posttranscriptional that plays crucial role various cellular processes. There two main types events: adenosine inosine (A-to-I) editing, catalyzed by ADARs on double-stranded or ADATs tRNA, cytosine uridine (C-to-U) APOBECs. This article provides overview structure, function, applications enzymes. We discuss structural characteristics three enzyme families their catalytic mechanisms also explain biological particularly innate immunity, cancer biogenesis, antiviral activity. Additionally, this describes tools for manipulating correct disease-causing mutations, as well potential enzymes field biotechnology therapy.

Language: Английский

Citations

11
MicroRNA-centered theranostics for pulmoprotection in critical COVID-19 DOI Creative Commons
Manel Perez‐Pons, Marta Molinero, Iván D. Benítez

et al.

Molecular Therapy — Nucleic Acids, Journal Year: 2024, Volume and Issue: 35(1), P. 102118 - 102118

Published: Jan. 10, 2024

Elucidating the pathobiological mechanisms underlying post-acute pulmonary sequelae following SARS-CoV-2 infection is essential for early interventions and patient stratification. Here, we investigated potential of microRNAs (miRNAs) as theranostic agents pulmoprotection in critical illness survivors. Multicenter study including 172 ICU Diffusion impairment was defined a lung-diffusing capacity carbon monoxide (D

Language: Английский

Citations

8