ArticleScience (New York, N.Y.)2021
Noncanonical transnitrosylation network contributes to synapse loss in Alzheimer's disease.
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Article in Science (New York, N.Y.), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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52 citing papers in PubMed.
- Early Retinal UCHL1 Dysregulation Coupled With Synaptic Loss Reflects Alzheimer's Disease Severity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Redox regulation of neuroinflammatory pathways contributes to damage in Alzheimer's disease brain.Cell chemical biology · 2026Article
- The Bright and Dark Sides of Nitric Oxide in Neurodegenerative Diseases.Journal of personalized medicine · 2026Review
- Ketogenic diet regulates Uch-L1(C) to improve cerebral energy metabolism and cognitive function in Alzheimer's disease mice.European journal of histochemistry : EJH · 2026Article
- Aberrant Protein S-Nitrosylation Mimics the Effect of Rare Genetic Mutations in Neurodegenerative Diseases.Journal of neurochemistry · 2026Review
- Nitric oxide‑mediated S‑Nitrosylation contributes to signaling transduction in human physiological and pathological status (Review).International journal of molecular medicine · 2025Review
- Gasotransmitter signaling in the brain: New frontiers for therapeutics.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Article
- Aberrant S-nitrosylation in the TCA cycle contributes to mitochondrial dysfunction, energy compromise, and synapse loss in neurodegenerative diseases.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Review
- Redox modulation of the complement cascade contributes to synapse loss in Alzheimer's disease.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Review
- UCH-L1 in Alzheimer's Disease: A Crucial Player in Dementia-Associated Mechanisms.International journal of molecular sciences · 2025Review
- FromActa pharmaceutica Sinica. B · 2025Article
- Neuroinflammation in Alzheimer disease.Nature reviews. Immunology · 2025Review
- Recent advances in the role of gasotransmitters in necroptosis.Apoptosis : an international journal on programmed cell death · 2025Review
- Shared early molecular mechanisms revealed in P301S and 5xFAD Alzheimer's disease mouse models.Translational psychiatry · 2025Article
- On-Chip Electrochemical Sensor Based on 3D Graphene Assembly Decorated Ultrafine RuCu Alloy Nanocatalyst for In Situ Detection of NO in Living Cells.Nanomaterials (Basel, Switzerland) · 2025Article
- S-Nitrosylation of CRTC1 in Alzheimer's disease impairs CREB-dependent gene expression induced by neuronal activity.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- diAcCA, a Pro-Drug for Carnosic Acid That Activates the Nrf2 Transcriptional Pathway, Shows Efficacy in the 5xFAD Transgenic Mouse Model of Alzheimer's Disease.Antioxidants (Basel, Switzerland) · 2025Article
- Female 3xTg-AD mice demonstrate hyperexcitability phenotype of Alzheimer's disease in structure-function and function-behavior relationships.Network neuroscience (Cambridge, Mass.) · 2025Article
- The transcriptional and cellular landscape of cognitive resilience to Alzheimer's disease.Frontiers in molecular neuroscience · 2025Review
- Redox regulation, protein S-nitrosylation, and synapse loss in Alzheimer's and related dementias.Neuron · 2024Review
Corrections and comments
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Authors and funding
13 authors.
Tomohiro Nakamura *Departments of Molecular Medicine and Neuroscience, and Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA 92037, USA. tnakamura@scripps.edu slipton@scripps.edu.ORCID https://orcid.org/0000-0002-4246-7771
Chang-Ki Oh *Departments of Molecular Medicine and Neuroscience, and Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA 92037, USA.ORCID https://orcid.org/0000-0003-2489-4072
Lujian LiaoDepartments of Molecular Medicine and Neuroscience, and Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
Xu ZhangDepartments of Molecular Medicine and Neuroscience, and Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
Kevin M LopezNeurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121, USA.ORCID https://orcid.org/0000-0003-0322-087X
Daniel GibbsDepartment of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA.
Amanda K DealDepartments of Molecular Medicine and Neuroscience, and Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
Henry R ScottDepartments of Molecular Medicine and Neuroscience, and Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA 92037, USA.ORCID https://orcid.org/0000-0002-4462-8479
Brian SpencerDepartment of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA.
Eliezer MasliahDepartment of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA.
Robert A RissmanDepartment of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA.
John R YatesDepartments of Molecular Medicine and Neuroscience, and Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA 92037, USA.ORCID https://orcid.org/0000-0001-5267-1672
Stuart A LiptonDepartments of Molecular Medicine and Neuroscience, and Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA 92037, USA. tnakamura@scripps.edu slipton@scripps.edu.ORCID https://orcid.org/0000-0002-3490-1259
Funding
UCSD Shiley-Marcos Alzheimer's Disease Research Center P30P30AG062429 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Steven Dyal Edland · 2019 to 2026
$34.9MTrainingP41GM103533 · NIGMS · UNIVERSITY OF WASHINGTON · PI MACCOSS, MICHAEL · 2012 to 2021
$20.7MProject 4: A Developmental Perspective to Nitrosative/Oxidative SusceptibilityP01ES016738 · NIEHS · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · PI LIPTON, STUART A · 2008 to 2012
$8.5MNovel Proteomics Approach to HIV-Associated Neurocognitive Disorder & Drug AbuseDP1DA041722 · NIDA · SCRIPPS RESEARCH INSTITUTE, THE · PI LIPTON, STUART A · 2016 to 2020
$7.0MB-Synuclein as a Treatment for Lewy Body DiseaseR01AG018440 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI RISSMAN, ROBERT · 2001 to 2021
$5.2MProject-002P30NS076411 · NINDS · SCINTILLON INSTITUTE FOR PHOTOBIOLOGY · PI LIPTON, STUART A · 2011 to 2016
$4.5MOmics Analyses of HIV and Substance Use DisorderR01DA048882 · NIDA · SCRIPPS RESEARCH INSTITUTE, THE · PI REPUNTE-CANONIGO, VEZ · 2019 to 2023
$4.3MNeuroimmune responses and therapeutics of alpha-synucleinopathies of the aging populationZIAAG000936 · NIA · NATIONAL INSTITUTE ON AGING · PI COOKSON, MARK · 2017 to 2025
$4.1MDynamic Interactions of the S-Nitrosoproteome in Type 2 Diabetes/Metabolic Syndrome and Alzheimer’s DiseaseRF1AG057409 · NIA · SCRIPPS RESEARCH INSTITUTE, THE · PI LIPTON, STUART A · 2017 to 2020
$4.1MS-Nitrosylation-Induced Posttranslational Modification and Aberrant Cell Signaling in Sporadic Alzheimer's DiseaseR01AG056259 · NIA · SCRIPPS RESEARCH INSTITUTE, THE · PI LIPTON, STUART A · 2017 to 2021
$3.3MNeuroprotective Mechanisms of S-Nitrosylated ApoE2 in Aging and Alzheimer's DiseaseR01AG061845 · NIA · SCRIPPS RESEARCH INSTITUTE, THE · PI NAKAMURA, TOMOHIRO · 2018 to 2022
$2.4MModeling Parkinson's Disease with Isogenic hiPSC-Derived Dopaminergic NeuronsR01NS086890 · NINDS · SCRIPPS RESEARCH INSTITUTE, THE · PI LIPTON, STUART A · 2014 to 2018
$2.1MBLRD VA I01 BX003040NIA NIH HHS P30 AG062429NIA NIH HHS R01 AG018440NIA NIH HHS R01 AG056259NIA NIH HHS R01 AG061845NIA NIH HHS R56 AG065372NIA NIH HHS RF1 AG057409NIDA NIH HHS DP1 DA041722NIDA NIH HHS R01 DA048882NIEHS NIH HHS P01 ES016738NIGMS NIH HHS P41 GM103533NINDS NIH HHS P30 NS076411NINDS NIH HHS R01 NS086890
Abstract
Here we describe mechanistically distinct enzymes (a kinase, a guanosine triphosphatase, and a ubiquitin protein hydrolase) that function in disparate biochemical pathways and can also act in concert to mediate a series of redox reactions. Each enzyme manifests a second, noncanonical function-transnitrosylation-that triggers a pathological biochemical cascade in mouse models and in humans with Alzheimer's disease (AD). The resulting series of transnitrosylation reactions contributes to synapse loss, the major pathological correlate to cognitive decline in AD. We conclude that enzymes with distinct primary reaction mechanisms can form a completely separate network for aberrant transnitrosylation. This network operates in the postreproductive period, so natural selection against such abnormal activity may be decreased.
Indexed as
Alzheimer DiseaseAmyloid beta-PeptidesAnimalsCyclin-Dependent Kinase 5CysteineDisease Models, AnimalDynaminsHEK293 CellsHumansMiceMice, TransgenicMutationNitric OxideNitric Oxide SynthaseNitroarginineOxidation-ReductionAmyloid beta-PeptidesCDK5 protein, humanCyclin-Dependent Kinase 5CysteineDNM1L protein, humanDynaminsNitric OxideNitric Oxide SynthaseNitroarginineUbiquitin ThiolesteraseUCHL1 protein, human
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