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

作　　者：Aina Bellver-Sanchis Pedro AAvila-López Iva Tic David Valle-García Marta Ribalta-Vilella Luis Labrador Deb Ranjan Banerjee Ana Guerrero Gemma Casadesus Coralie Poulard Mercè Pallàs Christian Grinán-Ferré 

机构地区：[1]Department of Pharmacology and Therapeutic Chemistry,Institut de Neurociències-Universitat de Barcelona,Barcelona,Spain [2]Department of Biochemistry and Molecular Genetics,Feinberg School of Medicine,Northwestern University,Chicago,IL,USA [3]Institute of Biotechnology,National Autonomous University of Mexico,Cuernavaca,Mexico [4]Department of Pharmacology and Therapeutics,Health Science Center-University of Florida,Gainesville,FL,USA [5]Department of Chemistry,National Institute of Technology Durgapur,M G Avenue,Durgapur,West Bengal,India [6]Cancer Research Cancer Lyon,Universitéde Lyon,Lyon,France [7]Inserm U1052,Centre de Recherche en Cancérologie de Lyon,Lyon,France [8]CNRS UMR5286,Centre de Recherche en Cancérlogie de Lyon,Lyon,France [9]Centro de Investigación en Red,Enfermedades Neurodegenerativas(CIBERNED),Instituto de Salud Carlos III,Madrid,Spain [10]Neuroimmunology Department,National Institute of Neurology and Neurosurgery“Manuel Velasco Suárez”,Mexico City,Mexico

出　　处：《Neural Regeneration Research》2024年第11期2532-2542,共11页中国神经再生研究（英文版）

基　　金：supported by the Ministerio de Economía,Industria y Competitividad(Agencia Estatal de Investigación,AEI,to CGF and MP);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);co-financed by Secretaria d’Universitats i Recerca del Departament d’Empresai Coneixement de la Generalitat de Catalunya 2021(Llavor 00086,to CGF);the recipient of an Alzheimer’s Association Research Fellowship(AARF-21-848511);the Agència de Gestiód’Ajuts Universitaris i de Recerca(AGAUR)for her FI-SDUR fellowship(2021FISDU 00182).

摘　　要：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 PPARγby 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/GADD45αpotentially 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.

关 键 词：aging cognitive decline epigenetics G9a inhibition microRNAs miR-128 peroxisome-proliferator activator receptorγ(PPARγ) PPARG SAMP8 

分 类 号：R749.16[医药卫生—神经病学与精神病学]