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Parkin is transcriptionally regulated by the aryl hydrocarbon receptor: Impact on α-synuclein protein levels.

Abstract：

: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.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

González-Barbosa E,García-Aguilar R,Vega L,Cabañas-Cortés MA,Gonzalez FJ,Segovia J,Morales-Lázaro SL,Cisneros B,Elizondo G

doi

10.1016/j.bcp.2019.08.002

subject

Has Abstract

pub_date

2019-10-01 00:00:00

pages

429-437

eissn

0006-2952

issn

1873-2968

pii

S0006-2952(19)30290-4

journal_volume

168

pub_type

杂志文章

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