An integrative systems-biology approach defines mechanisms of Alzheimer’s disease neurodegeneration DOI Creative Commons
Matthew Leventhal, Camila A. Zanella,

Byunguk Kang

и другие.

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Май 20, 2025

Despite years of intense investigation, the mechanisms underlying neuronal death in Alzheimer's disease, remain incompletely understood. To define relevant pathways, we conducted an unbiased, genome-scale forward genetic screen for age-associated neurodegeneration Drosophila. We also measured proteomics, phosphoproteomics, and metabolomics Drosophila models disease identified variants that modify gene expression disease-vulnerable neurons humans. then used a network model to integrate these data with previously published lipidomics genomics. Here, computationally predict experimentally confirm how HNRNPA2B1 MEPCE enhance toxicity tau protein, pathological feature disease. Furthermore, demonstrated hits CSNK2A1 NOTCH1 regulate DNA damage human stem cell-derived neural progenitor cells. Our study identifies candidate pathways could be targeted ameliorate

Язык: Английский

FlyBase: updates to theDrosophila melanogasterknowledge base DOI Creative Commons
Aoife Larkin, Steven J Marygold, Giulia Antonazzo

и другие.

Nucleic Acids Research, Год журнала: 2020, Номер 49(D1), С. D899 - D907

Опубликована: Окт. 22, 2020

FlyBase (flybase.org) is an essential online database for researchers using Drosophila melanogaster as a model organism, facilitating access to diverse array of information that includes genetic, molecular, genomic and reagent resources. Here, we describe the introduction several new features at FlyBase, including Pathway Reports, paralog information, disease models based on orthology, customizable tables within reports overview displays ('ribbons') expression data. We also variety recent important updates, incorporation developmental proteome, upgrades GAL4 search tab, additional Experimental Tool migration JBrowse genome browsing improvements batch queries/downloads Fast-Track Your Paper tool.

Язык: Английский

Процитировано

424
A large-scale resource for tissue-specific CRISPR mutagenesis in Drosophila DOI Creative Commons
Fillip Port,

Claudia Strein,

Mona Stricker

и другие.

eLife, Год журнала: 2020, Номер 9

Опубликована: Фев. 13, 2020

Genetic screens are powerful tools for the functional annotation of genomes. In context multicellular organisms, interrogation gene function is greatly facilitated by methods that allow spatial and temporal control abrogation. Here, we describe a large-scale transgenic short guide (sg) RNA library efficient CRISPR-based disruption specific target genes in constitutive or conditional manner. The consists currently more than 2600 plasmids 1700 fly lines with focus on targeting kinases, phosphatases transcription factors, each expressing two sgRNAs under Gal4/UAS system. We show CRISPR mutagenesis robust across many can be efficiently employed various somatic tissues, as well germline. order to prevent artefacts commonly associated excessive amounts Cas9 protein, have developed series novel UAS-Cas9 transgenes, which fine tuning expression achieve high editing activity without detectable toxicity. Functional assays, direct sequencing genomic sgRNA sites, indicates vast majority mediate disruption. Furthermore, conducted so far largest fully screen any metazoan organism, further supported efficiency accuracy our revealed uncharacterized essential development.

Язык: Английский

Процитировано

149
FlyBase: updates to the Drosophila genes and genomes database DOI Creative Commons
Arzu Öztürk-Çolak, Steven J Marygold, Giulia Antonazzo

и другие.

Genetics, Год журнала: 2024, Номер 227(1)

Опубликована: Фев. 1, 2024

Abstract FlyBase (flybase.org) is a model organism database and knowledge base about Drosophila melanogaster, commonly known as the fruit fly. Researchers from around world rely on genetic, genomic, functional information available in FlyBase, well its tools to view interrogate these data. In this article, we describe latest developments updates FlyBase. These include introduction of single-cell RNA sequencing data, improved content display information, updated orthology pipelines, new chemical reports, enhancements our outreach resources.

Язык: Английский

Процитировано

141
Pleiotropy, epistasis and the genetic architecture of quantitative traits DOI
Trudy F. C. Mackay, Robert R. H. Anholt

Nature Reviews Genetics, Год журнала: 2024, Номер 25(9), С. 639 - 657

Опубликована: Апрель 2, 2024

Язык: Английский

Процитировано

32
A versatile toolkit for CRISPR-Cas13-based RNA manipulation in Drosophila DOI Creative Commons
Nhan Huynh,

Noah Depner,

Raegan Larson

и другие.

Genome biology, Год журнала: 2020, Номер 21(1)

Опубликована: Ноя. 17, 2020

Abstract Advances in CRISPR technology have immensely improved our ability to manipulate nucleic acids, and the recent discovery of RNA-targeting endonuclease Cas13 adds even further functionality. Here, we show that works efficiently Drosophila , both ex vivo vivo. We test 44 different variants identify enzymes with best overall performance could target endogenous transcripts high efficiency specificity. also develop applications edit mRNAs mitochondrial transcripts. Our vector collection represents a versatile tool gene expression at post-transcriptional level.

Язык: Английский

Процитировано

87
Drosophila as a Model for Infectious Diseases DOI Open Access
J. Michael Harnish, Nichole Link, Shinya Yamamoto

и другие.

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(5), С. 2724 - 2724

Опубликована: Март 8, 2021

The fruit fly, Drosophila melanogaster, has been used to understand fundamental principles of genetics and biology for over a century. is now also considered an essential tool study mechanisms underlying numerous human genetic diseases. In this review, we will discuss how flies can be deepen our knowledge infectious disease in vivo. Flies make effective applicable models studying host-pathogen interactions thanks their highly conserved innate immune systems cellular processes commonly hijacked by pathogens. researchers possess the most powerful, rapid, versatile tools manipulation multicellular organisms. This allows robust experiments which specific pathogenic proteins expressed either one at time or conjunction with each other dissect molecular functions virulent factor cell-type-specific manner. Well documented phenotypes allow large pharmacological screens performed relative ease using huge collections mutant transgenic strains that are publicly available. These factors combine powerful dissecting out as well better treat diseases pose risks public health, including COVID-19, caused SARS-CoV-2.

Язык: Английский

Процитировано

59
Integrating non-mammalian model organisms in the diagnosis of rare genetic diseases in humans DOI
Shinya Yamamoto, Oguz Kanca, Michael F. Wangler

и другие.

Nature Reviews Genetics, Год журнала: 2023, Номер 25(1), С. 46 - 60

Опубликована: Июль 25, 2023

Язык: Английский

Процитировано

42
Sites of transcription initiation drive mRNA isoform selection DOI Creative Commons

Carlos Alfonso-Gonzalez,

Ivano Legnini,

Sarah Holec

и другие.

Cell, Год журнала: 2023, Номер 186(11), С. 2438 - 2455.e22

Опубликована: Май 1, 2023

The generation of distinct messenger RNA isoforms through alternative processing modulates the expression and function genes, often in a cell-type-specific manner. Here, we assess regulatory relationships between transcription initiation, splicing, 3′ end site selection. Applying long-read sequencing to accurately represent even longest transcripts from end, quantify mRNA Drosophila tissues, including transcriptionally complex nervous system. We find that heads, as well human cerebral organoids, choice is globally influenced by initiation (TSS). "Dominant promoters," characterized specific epigenetic signatures p300/CBP binding, impose transcriptional constraint define splice polyadenylation variants. In vivo deletion or overexpression dominant promoters loss disrupted landscape. Our study demonstrates crucial impact TSS on regulation transcript diversity tissue identity.

Язык: Английский

Процитировано

41
FlyRNAi.org—the database of the Drosophila RNAi screening center and transgenic RNAi project: 2021 update DOI Creative Commons
Yanhui Hu, Aram Comjean, Jonathan Rodiger

и другие.

Nucleic Acids Research, Год журнала: 2020, Номер 49(D1), С. D908 - D915

Опубликована: Окт. 7, 2020

Abstract The FlyRNAi database at the Drosophila RNAi Screening Center and Transgenic Project (DRSC/TRiP) provides a suite of online resources that facilitate functional genomics studies with special emphasis on melanogaster. Currently, provides: gene-centric ortholog mapping mining information about orthologs in common genetic model species; reagent-centric help researchers identify CRISPR sgRNA reagents or designs; data-centric visualization transcriptomics data, protein modification interactions, more. Here, we discuss updated new features biological biomedical efficiently identify, visualize, analyze, integrate data for other species. Together, these multiple steps workflows, from building gene reagent lists to management, analysis, integration data.

Язык: Английский

Процитировано

61
Infection and chronic disease activate a systemic brain-muscle signaling axis DOI
Shuo Yang, Meijie Tian,

Yulong Dai

и другие.

Science Immunology, Год журнала: 2024, Номер 9(97)

Опубликована: Июль 12, 2024

Infections and neurodegenerative diseases induce neuroinflammation, but affected individuals often show nonneural symptoms including muscle pain fatigue. The molecular pathways by which neuroinflammation causes pathologies outside the central nervous system (CNS) are poorly understood. We developed multiple models to investigate impact of CNS stressors on motor function found that Escherichia coli infections SARS-CoV-2 protein expression caused reactive oxygen species (ROS) accumulate in brain. ROS induced cytokine Unpaired 3 (Upd3) Drosophila its ortholog, IL-6, mice. CNS-derived Upd3/IL-6 activated JAK-STAT pathway skeletal muscle, mitochondrial dysfunction impaired function. observed similar phenotypes after expressing toxic amyloid-β (Aβ42) CNS. Infection chronic disease therefore activate a systemic brain-muscle signaling axis cytokines bypass connectome directly regulate physiology, highlighting IL-6 as therapeutic target treat disease-associated dysfunction.

Язык: Английский

Процитировано

8