Control of the neuroprotective Lipocalin Apolipoprotein D expression by alternative promoter regions and differentially expressed mRNA 5' UTR variants.
5' Untranslated Regions
Animals
Apolipoproteins D
/ genetics
Apolipoproteins E
/ genetics
Astrocytes
/ metabolism
Brain
/ cytology
Cell Line
Herbicides
/ toxicity
Lipocalins
/ genetics
Male
Mice
Mice, Inbred C57BL
Mutation
Oxidative Stress
Paraquat
/ toxicity
Promoter Regions, Genetic
RNA, Messenger
/ genetics
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2020
2020
Historique:
received:
12
12
2019
accepted:
03
06
2020
entrez:
20
6
2020
pubmed:
20
6
2020
medline:
2
9
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32559215
doi: 10.1371/journal.pone.0234857
pii: PONE-D-19-34292
pmc: PMC7304576
doi:
Substances chimiques
5' Untranslated Regions
0
Apolipoproteins D
0
Apolipoproteins E
0
Herbicides
0
Lipocalins
0
RNA, Messenger
0
Paraquat
PLG39H7695
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0234857Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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