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

Autor:	Parcon PA; Donald W. Reynolds Department of Geriatrics, Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR, USA., Balasubramaniam M; Donald W. Reynolds Department of Geriatrics, Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Geriatric Research Education and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA., Ayyadevara S; Donald W. Reynolds Department of Geriatrics, Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Geriatric Research Education and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA., Jones RA; Donald W. Reynolds Department of Geriatrics, Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Geriatric Research Education and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA., Liu L; Donald W. Reynolds Department of Geriatrics, Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR, USA., Shmookler Reis RJ; Donald W. Reynolds Department of Geriatrics, Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Geriatric Research Education and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA., Barger SW; Donald W. Reynolds Department of Geriatrics, Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Geriatric Research Education and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA., Mrak RE; Department of Pathology, University of Toledo Health Sciences Campus, Toledo, OH, USA., Griffin WST; Donald W. Reynolds Department of Geriatrics, Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Geriatric Research Education and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA. Electronic address: griffinsuet@uams.edu.
Jazyk:	angličtina
Zdroj:	Alzheimer's & dementia : the journal of the Alzheimer's Association [Alzheimers Dement] 2018 Feb; Vol. 14 (2), pp. 230-242. Date of Electronic Publication: 2017 Sep 22.
DOI:	10.1016/j.jalz.2017.07.754
Abstrakt:	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. (Published by Elsevier Inc.)
Databáze:	MEDLINE
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