Parkin is transcriptionally regulated by the aryl hydrocarbon receptor: Impact on α-synuclein protein levels.
Actins
/ metabolism
Animals
Brain
/ metabolism
Cell Line
Cytochrome P-450 CYP1A1
/ genetics
Gene Expression Regulation
/ physiology
Humans
Liver
/ metabolism
Mice
Mice, Knockout
Neurons
/ metabolism
RNA, Messenger
/ genetics
Receptors, Aryl Hydrocarbon
/ metabolism
Ubiquitin-Protein Ligases
/ genetics
alpha-Synuclein
/ genetics
Aryl hydrocarbon receptor
Parkin
Parkinson’s disease
TCDD
α-Synuclein
Journal
Biochemical pharmacology
ISSN: 1873-2968
Titre abrégé: Biochem Pharmacol
Pays: England
ID NLM: 0101032
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
12
06
2019
accepted:
07
08
2019
pubmed:
14
8
2019
medline:
7
7
2020
entrez:
13
8
2019
Statut:
ppublish
Résumé
Parkin (PRKN) is a ubiquitin E3 ligase that catalyzes the ubiquitination of several proteins. Mutations in the human Parkin gene, PRKN, leads to degeneration of dopaminergic (DA) neurons, resulting in autosomal recessive early-onset parkinsonism and the loss of PRKN function is linked to sporadic Parkinson's disease (PD). Additionally, several in vitro studies have shown that overexpression of exogenous PRKN protects against the neurotoxic effects induced by a wide range of cellular stressors, emphasizing the need to study the mechanism(s) governing PRKN expression and induction. Here, Prkn was identified as a novel target gene of the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor and member of the bHLH/PAS (basic helix-loop-helix/Per-Arnt-Sim) superfamily. AhR binds and transactivates the Prkn gene promoter. We also demonstrated that AhR is expressed in DA neurons and that its activation upregulates Prkn mRNA and protein levels in the mouse ventral midbrain. Additionally, the AhR-dependent increase in PRKN levels is associated with a decrease in the protein levels of its target substrate, α-synuclein, in an AhR-dependent manner, because this effect is not observed in Ahr-null mice. These results suggest that treatments designed to induce PRKN expression through the use of nontoxic AhR agonist ligands may be novel strategies to prevent and delay PD.
Identifiants
pubmed: 31404530
pii: S0006-2952(19)30290-4
doi: 10.1016/j.bcp.2019.08.002
pmc: PMC7376371
mid: NIHMS1610014
pii:
doi:
Substances chimiques
Actins
0
RNA, Messenger
0
Receptors, Aryl Hydrocarbon
0
alpha-Synuclein
0
Cyp1a1 protein, mouse
EC 1.14.14.1
Cytochrome P-450 CYP1A1
EC 1.14.14.1
Ubiquitin-Protein Ligases
EC 2.3.2.27
parkin protein
EC 2.3.2.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
429-437Subventions
Organisme : Intramural NIH HHS
ID : ZIA BC005562
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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