Neural Regeneration Research ›› 2024, Vol. 19 ›› Issue (11): 2532-2542.doi: 10.4103/1673-5374.393102

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Neuroprotective effects of G9a inhibition through modulation of peroxisome-proliferator activator receptor gamma-dependent pathways by miR-128

Aina Bellver-Sanchis1, Pedro A. Ávila-López2, Iva Tic1, David Valle-García3, †, Marta Ribalta-Vilella1, Luis Labrador4, #br# Deb Ranjan Banerjee5, Ana Guerrero1, Gemma Casadesus4, Coralie Poulard6, 7, 8, Mercè Pallàs1, 9, Christian Griñán-Ferré1, 9, *#br#   

  1. 1Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Barcelona, Spain; 2Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; 3Institute of Biotechnology, National Autonomous University of Mexico, Cuernavaca, Mexico; 4Department of Pharmacology and Therapeutics, Health Science Center-University of Florida, Gainesville, FL, USA; 5Department of Chemistry, National Institute of Technology Durgapur, M G Avenue, Durgapur, West Bengal, India; 6Cancer Research Cancer Lyon, Université de Lyon, Lyon, France; 7Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France; 8CNRS UMR5286, Centre de Recherche en Cancérlogie de Lyon, Lyon, France; 9Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
    †Current address: Neuroimmunology Department, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Mexico City, Mexico
  • Online:2024-11-15 Published:2024-03-29
  • Contact: Christian Griñán-Ferré, PhD, Christian.grinan@ub.edu.
  • Supported by:
    This study was supported by the Ministerio de Economía, Industria y Competitividad (Agencia Estatal de Investigación, AEI; to CGF and MP) and Fondo Europeo de Desarrollo Regional (MINECO-FEDER) (PID2022-139016OA-I00, PDC2022-133441-I00; to CGF and MP), Generalitat de Catalunya (2021 SGR 00357; to CGF and MP). This study was co-financed by Secretaria d’Universitats i Recerca del Departament d’Empresai Coneixement de la Generalitat de Catalunya 2021 (Llavor 00086; to CGF). AG is the recipient of an Alzheimer’s Association Research Fellowship (AARF-21-848511). ABS acknowledges the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) for her FI-SDUR fellowship (2021FISDU 00182).

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Abstract: Dysregulation of G9a, a histone-lysine N-methyltransferase, has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress. Likewise, microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis, especially in multifactorial diseases such as Alzheimer’s disease. Therefore, our aim has been to provide partial insights into the interconnection between G9a, microRNAs, oxidative stress, and neuroinflammation. To better understand the biology of G9a, we compared the global microRNA expression between senescence-accelerated mouse-prone 8 (SAMP8) control mice and SAMP8 treated with G9a inhibitor UNC0642. We found a downregulation of miR-128 after a G9a inhibition treatment, which interestingly binds to the 3′ untranslated region (3′-UTR) of peroxisome-proliferator activator receptor γ (PPARG) mRNA. Accordingly, Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control group. We also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a inhibitor. To confirm these antioxidant effects, we treated primary neuron cell cultures with hydrogen peroxide as an oxidative insult. In this setting, treatment with G9a inhibitor increases both cell survival and antioxidant enzymes. Moreover, up-regulation of PPARγ by G9a inhibitor could also increase the expression of genes involved in DNA damage responses and apoptosis. In addition, we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers expression. Finally, PPARγ/GADD45α potentially contributes to enhancing synaptic plasticity and neurogenesis after G9a inhibition. Altogether, we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due, at least in part, by the modulation of PPARγ-dependent pathways by miR-128.

Key words: aging, cognitive decline, epigenetics, G9a inhibition, microRNAs, miR-128, peroxisome-proliferator activator receptor γ (PPARγ), PPARG, SAMP8