Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs

Alzheimer's & Dementia - Tập 14 Số 2 - Trang 230-242 - 2018
Paul A. Parcon1, Meenakshisundaram Balasubramaniam1,2, Srinivas Ayyadevara1,2, Richard A. Jones1,2, Ling Liu1, Robert J. Shmookler Reis1,2, Steven W. Barger1,2, Robert E. Mrak3, W. Sue T. Griffin1,2
1Donald W. Reynolds Department of Geriatrics, Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR, USA
2Geriatric Research Education and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA
3Department of Pathology, University of Toledo Health Sciences Campus, Toledo, OH, USA

Tóm tắt

AbstractIntroductionAlzheimer apolipoprotein E (APOE) ɛ4/ɛ4 carriers have earlier disease onset and more protein aggregates than patients with other APOE genotypes. Autophagy opposes aggregation, and important autophagy genes are coordinately regulated by transcription factor EB (TFEB) binding to “coordinated lysosomal expression and regulation” (CLEAR) DNA motifs.MethodsAutophagic gene expression was assessed in brains of controls and Alzheimer's disease (AD) patients parsed by APOE genotype and in a glioblastoma cell line expressing either apoE3 or apoE4. Computational modeling assessed interactions between apoE and mutated apoE with CLEAR or modified DNA.ResultsThree TFEB‐regulated mRNA transcripts—SQSTM, MAP1LC3B, and LAMP2—were lower in AD ɛ4/ɛ4 than in AD ɛ3/ɛ3 brains. Computational modeling predicted avid specific binding of apoE4 to CLEAR motifs. ApoE was found in cellular nuclei, and in vitro binding assays suggest competition between apoE4 and TFEB at CLEAR sites.ConclusionApoE4‐CLEAR interactions may account for suppressed autophagy in APOE ɛ4/ɛ4 carriers and, in this way, contribute to earlier AD onset.

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Tài liệu tham khảo

10.1073/pnas.92.11.4725

Roses AD, 1995, Apolipoprotein E E4 allele and risk of dementia, Jama, 273, 374, 10.1001/jama.1995.03520290026015

10.1038/ng1934

10.1038/nrneurol.2011.2

10.1016/j.jsbmb.2016.03.012

10.1056/NEJM199511093331902

10.1007/s00401-010-0666-1

10.1111/acel.12501

10.3389/fncel.2015.00103

10.1038/nm.3232

10.1093/jnen/64.2.113

10.1016/S0002-9440(10)64538-5

10.1523/JNEUROSCI.6412-10.2011

DJColacurcio RANixon.Disorders of lysosomal acidification‐The emerging role of v‐ATPase in aging and neurodegenerative disease. Ageing Res Rev2016

10.1111/ejn.12169

10.1089/dna.2014.2738

10.1523/JNEUROSCI.0705-15.2015

10.15252/emmm.201303671

10.1126/science.1204592

10.1093/hmg/ddr306

10.1371/journal.pone.0056526

10.1523/JNEUROSCI.3562-15.2016

10.1016/j.neurobiolaging.2016.10.005

NEswar BWebb MAMarti‐Renom MSMadhusudhan DEramian MYShen et al.Comparative protein structure modeling using Modeller. Curr Protoc Bioinformatics2006 Chapter 5:Unit 5 6

Schrodinger LLC. The PyMOL Molecular Graphics System Version 1.8. 2015.

10.1002/jcc.20291

10.1111/jnc.13526

10.1038/ncb3114

Badia MC, 2013, Lymphocytes from young healthy persons carrying the ApoE4 allele overexpress stress‐related proteins involved in the pathophysiology of Alzheimer's disease, J Alzheimers Dis, 33, 77, 10.3233/JAD-2012-120973

10.1080/15548627.2015.1100356

10.1016/j.nbd.2013.10.018

10.1023/A:1002861008363

10.1042/BJ20031352

10.1042/BJ20071261

10.1093/nar/gkq311

Huang Y, 2014, Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases, Neurobiol Dis, 72, 3, 10.1016/j.nbd.2014.08.025

10.1074/jbc.M110.151084

10.1063/1.4897978

10.1371/journal.pone.0120635

10.1074/jbc.M112.420224

10.3233/JAD-151101

10.1038/nature24016

10.3389/fimmu.2013.00083

10.1186/1742-2094-3-5

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Alzheimer's & Dementia

Tập 14 Số 2

230-242

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