ArticleNature aging2022
Alzheimer's disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment.
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Article in Nature aging, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers, 1 of them a synthesis that pooled it.
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40citing papers in PubMed, 1 pooled it
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Who cites it
40 citing papers in PubMed, 1 synthesis or guideline pooled it, 52 citations in OpenAlex.
- Dissecting Detergent-Insoluble Proteome in Alzheimer's Disease by TMTc-Corrected Quantitative Mass Spectrometry.Molecular & cellular proteomics : MCP · 2023Pooled it
- Disruptions in RNA Splicing: A Key Regulator of Cognitive Impairment in Perioperative Neurocognitive Disorders.Neuroscience bulletin · 2026Review
- U1 Small Nuclear Ribonucleoprotein Autoantibodies Reflect the Disruption of the Blood-Nerve Barrier in Guillain-Barré Syndrome.International journal of molecular sciences · 2026Article
- The aging genome exhibits organized vulnerability to somatic mutations.bioRxiv : the preprint server for biology · 2026Article
- Article
- Decoding Alzheimer's Disease One Cell Class at a Time.Cellular and molecular neurobiology · 2026Review
- Comprehensive Human Red Blood Cell Membrane and Cytoplasmic Proteome Analyses.Scientific data · 2026Article
- Cell type-resolved proteomics reveals intra- and intercellular signaling in Alzheimer's disease.bioRxiv : the preprint server for biology · 2026Article
- SMR Analysis Integrating GWAS and eQTL Data Reveals UHRF1BP1 and SNRPC as Potential Drug Targets for Low Back Pain.Journal of pain research · 2026Article
- Proteomic Insight Into Alzheimer's Disease Pathogenesis Pathways.Proteomics · 2025Review
- Midkine attenuates amyloid-β fibril assembly and plaque formation.Nature structural & molecular biology · 2025Article
- RNA dysfunction in age-related macular degeneration: the role of U1 snRNP complex and neurodegenerative diseases.International journal of retina and vitreous · 2025Review
- Splicing factor Sf3b1 facilitates maintenance of neuronal dendrites by modulating mitochondrial health.Cellular and molecular life sciences : CMLS · 2025Article
- SFRS8 Regulates Memory by Modulating RNA Splicing of Synaptic Genes.Molecular neurobiology · 2025Article
- Differential effects of age and sex on tau pathology propagation in the htau mouse model: A neuropathological and proteomic study.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Early Dysregulation of RNA Splicing and Translation Processes Are Key Markers from Mild Cognitive Impairment to Alzheimer's Disease: An In Silico Transcriptomic Analysis.International journal of molecular sciences · 2025Article
- Proteomic landscape of Alzheimer's disease: emerging technologies, advances and insights (2021 - 2025).Molecular neurodegeneration · 2025Review
- Beta cells to brain cells: The pivotal role of insulin and glucose metabolism in Alzheimer's disease.Neuroprotection (Chichester, England) · 2025Review
- Characterizing the expression profile of 3R tau pathology in Pick's disease.Science advances · 2025Article
- Human and mouse proteomics reveals the shared pathways in Alzheimer's disease and delayed protein turnover in the amyloidome.Nature communications · 2025Article
Corrections and comments
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Authors and funding
40 authors at 6 institutions in 2 countries.
Ping-Chung ChenDepartment of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Xian HanDepartment of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Timothy I ShawCenter for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Yingxue FuDepartment of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Huan SunDepartment of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Mingming NiuDepartment of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Zhen WangDepartment of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Yun JiaoDepartment of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Brett J W TeubnerDepartment of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Donnie EddinsDepartment of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Lauren N BeloateDepartment of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Bing BaiDepartment of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Joseph MertzDepartment of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Yuxin LiDepartment of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Ji-Hoon ChoCenter for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Xusheng WangIntegrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Zhiping WuDepartment of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Danting LiuDepartment of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Suresh PoudelDepartment of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Zuo-Fei YuanCenter for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Ariana MancieriDepartment of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Jonathan LowDepartment of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Hyeong-Min LeeDepartment of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Mary H PattonDepartment of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Laurie R EarlsDepartment of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Elizabeth StewartDepartment of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Peter VogelVeterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Yawei HuiCenter for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Shibiao WanCenter for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
David A BennettDepartment of Neurological Sciences, Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
Geidy E SerranoBanner Sun Health Research Institute, Sun City, AZ 85351, USA.
Thomas G BeachBanner Sun Health Research Institute, Sun City, AZ 85351, USA.
Michael A DyerDepartment of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Richard J SmeyneDepartment of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Tudor MoldoveanuDepartment of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Taosheng ChenDepartment of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Gang WuDepartment of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Stanislav S ZakharenkoDepartment of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Gang YuDepartment of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Junmin PengDepartment of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
St. Jude Children's Research Hospital · USBanner Sun Health Research Institute · USPennsylvania State University · USRush University Medical Center · USSouthwestern Medical Center · USUniversity of Tennessee Health Science Center · US
Funding
SUPPLEMENT TO RUSH ALZHEIMERS DISEASE CENTER COREP30AG010161 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI LEURGANS, SUE E. · 1991 to 2020
$49.1MEPIDEMIOLOGY OF NEURAL RESERVE AND NEUROBIOLOGY IN AGINGR01AG017917 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 2001 to 2023
$43.3MProject 4 (Genetic modifiers for APOE-associated Alzheimer's disease pathogenesis)U19AG069701 · NIA · MAYO CLINIC JACKSONVILLE · PI ALISON M GOATE, DAVID M. HOLTZMAN · 2021 to 2026
$42.0MResearch Education ComponentP30AG019610 · NIA · SUN HEALTH RESEARCH INSTITUTE · PI REIMAN, ERIC MICHAEL · 2001 to 2020
$32.5MResearch Education ComponentP30AG072980 · NIA · BANNER HEALTH · PI Nicholas Ashton · 2021 to 2026
$24.9MRush Alzheimer's Disease Research CenterP30AG072975 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI Lisa L Barnes, Julie A. Schneider · 2021 to 2026
$24.7MRISK FACTORS, PATHOLOGY, AND CLINICAL EXPRESSIONS OF ADR01AG015819 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 1998 to 2024
$21.4MUtilization of proteomics and lipidomics to identify modifiers of LBDU54NS110435 · NINDS · MAYO CLINIC JACKSONVILLE · PI DICKSON, DENNIS WILLIAM · 2019 to 2023
$14.5MNational Brain and Tissue Resource for Parkinson's Disease and Related DisordersU24NS072026 · NINDS · BANNER SUN HEALTH RESEARCH INSTITUTE · PI BEACH, THOMAS G · 2011 to 2015
$7.8MSystems Approaches to Novel Molecular Mechanism in Alzheimer's DiseaseRF1AG064909 · NIA · UT SOUTHWESTERN MEDICAL CENTER · PI PENG, JUNMIN, YU, GANG · 2019 to 2024
$6.4MDissecting neuron-microglia-astrocyte interaction in AD pathogenesisRF1AG068581 · NIA · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI PENG, JUNMIN, ROSSOLL, WILFRIED · 2020 to 2023
$5.4MTowards understanding cellular mechanisms of positive symptoms of schizophreniaR01MH097742 · NIMH · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI ZAKHARENKO, STANISLAV S · 2013 to 2022
$4.1MNIA NIH HHS P30 AG010161NIA NIH HHS P30 AG019610NIA NIH HHS P30 AG072975NIA NIH HHS P30 AG072980NIA NIH HHS R01 AG015819NIA NIH HHS R01 AG017917NIA NIH HHS R01 AG047928NIA NIH HHS R01 AG053987NIA NIH HHS R01 AG068581NIA NIH HHS RF1 AG064909NIA NIH HHS RF1 AG068581NIA NIH HHS U19 AG069701NIMH NIH HHS R01 MH095810NIMH NIH HHS R01 MH097742NINDS NIH HHS U24 NS072026NINDS NIH HHS U54 NS110435
Abstract
Recent proteome and transcriptome profiling of Alzheimer's disease (AD) brains reveals RNA splicing dysfunction and U1 small nuclear ribonucleoprotein (snRNP) pathology containing U1-70K and its N-terminal 40-KDa fragment (N40K). Here we present a causative role of U1 snRNP dysfunction to neurodegeneration in primary neurons and transgenic mice (N40K-Tg), in which N40K expression exerts a dominant-negative effect to downregulate full-length U1-70K. N40K-Tg recapitulates N40K insolubility, erroneous splicing events, neuronal degeneration and cognitive impairment. Specifically, N40K-Tg shows the reduction of GABAergic synapse components (e.g., the GABA receptor subunit of GABRA2), and concomitant postsynaptic hyperexcitability that is rescued by a GABA receptor agonist. Crossing of N40K-Tg and the 5xFAD amyloidosis model indicates that the RNA splicing defect synergizes with the amyloid cascade to remodel the brain transcriptome and proteome, deregulate synaptic proteins, and accelerate cognitive decline. Thus, our results support the contribution of U1 snRNP-mediated splicing dysfunction to AD pathogenesis.
Indexed as
Alzheimer DiseaseCognitive DysfunctionAnimalsMiceProteomeRibonucleoprotein, U1 Small NuclearRNA SplicingProteomeRibonucleoprotein, U1 Small Nuclear
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