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Control of the neuroprotective Lipocalin Apolipoprotein D expression by alternative promoter regions and differentially expressed mRNA 5’ UTR variants

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Díez Hernando, Sergio and Mejías, Andrés and Sánchez, Diego and Gutiérrez Pozo, Gabriel and Ganfornina, María D. (2020) Control of the neuroprotective Lipocalin Apolipoprotein D expression by alternative promoter regions and differentially expressed mRNA 5’ UTR variants. PLoS One, 15 (6). pp. 1-19. ISSN ESSN: 1932-6203

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Official URL: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234857



Abstract

The Lipocalin Apolipoprotein D (ApoD) is one of the few genes consistently overexpressed in the aging brain, and in most neurodegenerative and psychiatric diseases. Its functions include metabolism regulation, myelin management, neuroprotection, and longevity regulation. Knowledge of endogenous regulatory mechanisms controlling brain disease-triggered ApoD expression is relevant if we want to boost pharmacologically its neuroprotecting potential. In addition to classical transcriptional control, Lipocalins have a remarkable variability in mRNA 5’UTR-dependent translation efficiency. Using bioinformatic analyses, we uncover strong selective pressures preserving ApoD 5’UTR properties, indicating unexpected functional conservation. PCR amplifications demonstrate the production of five 5’UTR variants (A-E) in mouse ApoD, with diverse expression levels across tissues and developmental stages. Importantly, Variant E is specifically expressed in the oxidative stress-challenged brain. Predictive analyses of 5’UTR secondary structures and enrichment in elements restraining translation, point to Variant E as a tight regulator of ApoD expression. We find two genomic regions conserved in human and mouse ApoD: a canonical (α) promoter region and a previously unknown region upstream of Variant E that could function as an alternative mouse promoter (β). Luciferase assays demonstrate that both α and β promoter regions can drive expression in cultured mouse astrocytes, and that Promoter β activity responds proportionally to incremental doses of the oxidative stress generator Paraquat. We postulate that Promoter β works in association with Variant E 5’UTR as a regulatory tandem that organizes ApoD gene expression in the nervous system in response to oxidative stress, the most common factor in aging and neurodegeneration.


Item Type:Article
Uncontrolled Keywords:Lipocalin Apolipoprotein D; mRNA 5’ UTR variants
Subjects:Medical sciences > Biology > Molecular biology
Medical sciences > Biology > Biomathematics
Medical sciences > Biology > Neurosciences
ID Code:62507
Deposited On:13 Oct 2020 08:20
Last Modified:14 Oct 2020 07:33

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