RESUMEN
Parkinson's disease (PD) is a neurodegenerative disease characterized by the selective loss of dopaminergic neurons in the substantia nigra (SN). In a previous study, the authors demonstrated that ferritin heavy chain 1 (FTH1) inhibited ferroptosis in a model of 6hydroxydopamine (6OHDA)induced PD. However, whether and how microRNAs (miRNAs/miRs) modulate FTH1 in PD ferroptosis is not yet well understood. In the present study, in vivo and in vitro models of PD induced by 6OHDA were established. The results in vivo and in vitro revealed that the levels of the ferroptosis marker protein, glutathione peroxidase 4 (GPX4), and the PD marker protein, tyrosine hydroxylase (TH), were decreased in the model group, associated with a decreased FTH1 expression and the upregulation of miR335. In both the in vivo and in vitro models, miR335 mimic led to a lower FTH1 expression, exacerbated ferroptosis and an enhanced PD pathology. The luciferase 3'untranslated region reporter results identified FTH1 as the direct target of miR335. The silencing of FTH1 in 6OHDAstimulated cells enhanced the effects of miR335 on ferroptosis and promoted PD pathology. Mechanistically, miR335 enhanced ferroptosis through the degradation of FTH1 to increase iron release, lipid peroxidation and reactive oxygen species (ROS) accumulation, and to decrease mitochondrial membrane potential (MMP). On the whole, the findings of the present study reveal that miR335 promotes ferroptosis by targeting FTH1 in in vitro and in vivo models of PD, providing a potential therapeutic target for the treatment of PD.
Asunto(s)
Apoferritinas/metabolismo , Ferroptosis/genética , MicroARNs/genética , Enfermedad de Parkinson/patología , Animales , Modelos Animales de Enfermedad , Hierro/metabolismo , Peroxidación de Lípido/fisiología , Masculino , Potencial de la Membrana Mitocondrial/fisiología , Oxidopamina/toxicidad , Fosfolípido Hidroperóxido Glutatión Peroxidasa/análisis , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Tirosina 3-Monooxigenasa/análisisRESUMEN
There is rising concern for the interaction of environmental contaminants with brain transcriptome and the potential effect on reproductive processes. The present study sought to determine selenoprotein glutathione peroxidase 4 (gpx4) transcriptional activity in the brain and testis of the soil biosentinel, Podarcis sicula, through the main phases of the reproductive cycle and whether pharmaceuticals exert an endocrine disruption. Based on gpx4 cloned amminoacids sequence (GenBank AEX09236.1.), we used a bioinformatic approach to assess the structural role. Specifically, we detected seasonally the reactive oxygen species (ROS) level using electron spin resonance spectroscopy and gpx4 transcriptional activity using quantitative real-time polymerase chain reaction. In addition, the impact of pharmaceuticals was assessed after 21-days of treatment with ICI 182,780 and human chorionic gonadotropin administration in mating and winter stasis, respectively. Bioinformatic data shows the gpx4 proteic activity and a phylogenetic profile. ROS contents in lizard brain are significantly less than in testis and display higher levels after treatments. Brain gpx4 expression gives statistically significant seasonal differences, opposite trends in testis and altered expression in both tissues, with evidence of testis morphological and DNA disruption. Taken together, these results provide direct evidence that gpx4 in P. sicula plays a seasonal regulatory role and may be a reliable biomarker for reproductive health toxicity screening.