RESUMO
Rotenone is a pesticide commonly used in agriculture that is associated with the risk of developing Parkinson's disease (PD) by inducing mitochondrial damage. As a protective cell response to different challenges, they activate mitophagy, which involves parkin activity. Parkin is an E3 ubiquitin ligase necessary in the initial steps of mitophagy, and its overexpression protects against parkinsonian effects in different models. Recent studies have reported that the aryl hydrocarbon receptor (AHR), a ligand-dependent transcription factor, induces parkin expression. Kynurenine, an endogenous AHR ligand, promotes neuroprotection in chronic neurodegenerative disorders, such as PD, although its neuroprotective mechanism needs to be fully understood. Therefore, we evaluated whether the overexpression of parkin by AHR activation with kynurenine promotes autophagy and reduces the neurotoxicity induced by rotenone in SH-SY5Y cells differentiated to dopaminergic neurons. SH-SY5Y neurons were treated with rotenone or pretreated with kynurenine or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and parkin levels, apoptosis, mitochondrial potential membrane, and autophagy were determined. The results showed that kynurenine and TCDD treatments induced parkin expression in an AHR-dependent manner. Kynurenine pretreatment inhibited rotenone-induced neuronal apoptosis in 17%, and the loss of mitochondrial membrane potential in 30% when compare to rotenone alone, together with a decrease in autophagy. By contrast, although TCDD treatment increased parkin levels, non-neuroprotective effects were observed. The kynurenine protective activity was AHR independent, suggesting that parkin induction might not be related to this effect. On the other hand, kynurenine treatment inhibited alpha amine-3-hydroxy-5-methyl-4-isoxazol propionic acid and N-methyl-D-aspartate receptors, which are well-known excitotoxicity mediators activated by rotenone exposure.
Assuntos
Neuroblastoma , Fármacos Neuroprotetores , Doença de Parkinson , Dibenzodioxinas Policloradas , Humanos , Rotenona , Cinurenina/farmacologia , Receptores de Hidrocarboneto Arílico , Ligantes , Morte Celular , Apoptose , Ubiquitina-Proteína Ligases/metabolismo , Linhagem Celular Tumoral , Fármacos Neuroprotetores/farmacologiaRESUMO
Parkin is a cytosolic E3 ubiquitin ligase that plays an important role in neuroprotection by targeting several proteins to be degraded by the 26S proteasome. Its dysfunction has been associated not only with Parkinson's disease (PD) but also with other neurodegenerative pathologies, such as Alzheimer's disease and Huntington's disease. More recently, Parkin has been identified as a tumor suppressor gene implicated in cancer development. Due to the important roles that this E3 ubiquitin ligase plays in cellular homeostasis, its expression, activity, and turnover are tightly regulated. Several reviews have addressed Parkin regulation; however, genetic and epigenetic regulation have been excluded. In addition to posttranslational modifications (PTMs), this review examines the regulatory mechanisms that control Parkin function through gene expression, epigenetic regulation, and degradation. Furthermore, the consequences of disrupting these regulatory processes on human health are discussed.
Assuntos
Sobrevivência Celular/fisiologia , Regulação da Expressão Gênica/fisiologia , Neoplasias/metabolismo , Neurônios/fisiologia , Ubiquitina-Proteína Ligases/metabolismo , Animais , Humanos , Ubiquitina-Proteína Ligases/genéticaRESUMO
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.