Parkin is Transcriptionally Regulated by the Aryl Hydrocarbon Receptor: Impact on α-Synuclein Protein Levels

摘要: Parkin (PRKN) is a ubiquitin E3 ligase that catalyzes the ubiquitination of several proteins. Mutations in human gene, PRKN, leads to degeneration dopaminergic (DA) neurons, resulting autosomal recessive early-onset parkinsonism and loss PRKN function linked sporadic Parkinson's disease (PD). Additionally, vitro studies have shown overexpression exogenous protects against neurotoxic effects induced by wide range cellular stressors, emphasizing need study mechanism(s) governing expression induction. Here, Prkn was identified as novel target gene aryl hydrocarbon receptor (AhR), ligand-activated transcription factor member bHLH/PAS (basic helix-loop-helix/Per-Arnt-Sim) superfamily. AhR binds transactivates promoter. We also demonstrated expressed DA neurons its activation upregulates mRNA protein levels mouse ventral midbrain. AhR-dependent increase associated with decrease substrate, α-synuclein, an manner, because this effect not observed Ahr-null mice. These results suggest treatments designed induce through use nontoxic agonist ligands may be strategies prevent delay PD.