Alzheimer's & dementia : the journal of the Alzheimer's Association · 2017
Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПоддержка правительства СШАVideo-Audio MediaНазвание и аннотация: Перевод пока не подготовлен
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Parcon Paul A, Balasubramaniam Meenakshisundaram, Ayyadevara Srinivas, Jones Richard A, Liu Ling, Shmookler Reis Robert J, Barger Steven W, Mrak Robert E, Griffin W Sue T
Аннотация
INTRODUCTION: Alzheimer 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.
METHODS: Autophagic 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.
RESULTS: Three 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.
CONCLUSION: ApoE4-CLEAR interactions may account for suppressed autophagy in APOE ɛ4/ɛ4 carriers and, in this way, contribute to earlier AD onset.
METHODS: Autophagic 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.
RESULTS: Three 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.
CONCLUSION: ApoE4-CLEAR interactions may account for suppressed autophagy in APOE ɛ4/ɛ4 carriers and, in this way, contribute to earlier AD onset.
Предметные рубрики MeSH
Alzheimer DiseaseApolipoprotein E3Apolipoprotein E4AutophagyBasic Helix-Loop-Helix Leucine Zipper Transcription FactorsBrainCell Line, TransformedComputer SimulationCytokinesDisease ProgressionElectrophoretic Mobility Shift AssayEpistasis, GeneticFemaleGenotypeHumansLysosomesMaleModels, MolecularMolecular Docking SimulationNucleotide MotifsProtein BindingRNA, Messenger