ArticleAging and disease2024
G9a Inhibition Promotes Neuroprotection through GMFB Regulation in Alzheimer's Disease.
Article in Aging and disease, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 19 citations in OpenAlex.
- Epigenetic regulators polyphenols in neurodegenerative diseases: a promising intervention strategy.Annals of medicine · 2026Review
- Repurposing antifolates as G9a methyltransferase inhibitors for potential Alzheimer's disease therapeutics via 3D QSAR/pharmacophore mapping and experimental validations.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Article
- Repurposing antifolates as G9a methyltransferase inhibitors for potential Alzheimer's disease therapeutics via 3D QSAR/pharmacophore mapping and experimental validations.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Article
- Irisin-BDNF axis mediates muscle-brain communication: a complete molecular cascade and potential bidirectional feedback from peripheral activation to central protection.Biogerontology · 2026Review
- DiSPA: differential substructure-pathway attention for drug response prediction.Bioinformatics (Oxford, England) · 2026Article
- The dual G9a inhibitor and histamine H3 receptor antagonist A-366 improves repetitive and social behaviors and attenuates neuroinflammation in BTBR T + tf/J mice.Scientific reports · 2026Article
- G9a Targeting by miR-122 Ameliorates Ischemic Brain Injury via Enhanced Microglial Autophagy and Suppressed Ferroptosis.Neurochemical research · 2026Article
- The H3K9me2-FOXG1-microRNA axis reduces cochlear hair cells damage by modulating autophagy in age-related hearing loss.Frontiers in molecular neuroscience · 2026Article
- Epigenetics in Alzheimer's disease: from molecular mechanisms to emerging novel biomarkers.Frontiers in aging neuroscience · 2026Review
- Targeting Histone H3K9 Methyltransferase G9a as a Potential Therapeutic Strategy for Neuropsychiatric Disorders.Medicinal research reviews · 2025Review
- Epigenetic Regulation of Aging and its Rejuvenation.MedComm · 2025Review
- Neuroprotective effects of G9a inhibition and cannabinoid receptor activation in Alzheimer's disease through a pharmacological approach.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Article
- Development of a brain-penetrant G9a methylase inhibitor to target Alzheimer's disease-associated proteopathology.Nature communications · 2025Article
- G9a an Epigenetic Therapeutic Strategy for Neurodegenerative Conditions: From Target Discovery to Clinical Trials.Medicinal research reviews · 2025Review
- Impact of Neuroimmune System Activation by Adolescent Binge Alcohol Exposure on Adult Neurobiology.Advances in experimental medicine and biology · 2025Review
- Repurposing of Raltitrexed as an Effective G9a/EHMT2 Inhibitor and Promising Anti-Alzheimer's Agent.ACS medicinal chemistry letters · 2023Article
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Authors and funding
17 authors at 9 institutions in 7 countries.
Funding
Abstract
Epigenetic alterations are a fundamental pathological hallmark of Alzheimer's disease (AD). Herein, we show the upregulation of G9a and H3K9me2 in the brains of AD patients. Interestingly, treatment with a G9a inhibitor (G9ai) in SAMP8 mice reversed the high levels of H3K9me2 and rescued cognitive decline. A transcriptional profile analysis after G9ai treatment revealed increased gene expression of glia maturation factor β (GMFB) in SAMP8 mice. Besides, a H3K9me2 ChIP-seq analysis after G9a inhibition treatment showed the enrichment of gene promoters associated with neural functions. We observed the induction of neuronal plasticity and a reduction of neuroinflammation after G9ai treatment, and more strikingly, these neuroprotective effects were reverted by the pharmacological inhibition of GMFB in mice and cell cultures; this was also validated by the RNAi approach generating the knockdown of GMFB/Y507A.10 in Caenorhabditis elegans. Importantly, we present evidence that GMFB activity is controlled by G9a-mediated lysine methylation as well as we identified that G9a directly bound GMFB and catalyzed the methylation at lysine (K) 20 and K25 in vitro. Furthermore, we found that the neurodegenerative role of G9a as a GMFB suppressor would mainly rely on methylation of the K25 position of GMFB, and thus G9a pharmacological inhibition removes this methylation promoting neuroprotective effects. Then, our findings confirm an undescribed mechanism by which G9a inhibition acts at two levels, increasing GMFB and regulating its function to promote neuroprotective effects in age-related cognitive decline.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.