Autophagy Stimulation Decreases Dopaminergic Neuronal Death Mediated by Oxidative Stress

• Published in: Molecular neurobiology Vol. 56; no. 12; pp. 8136 - 8156
• Main Authors: Ramirez-Moreno, Marcela J., Duarte-Jurado, Ana P., Gopar-Cuevas, Yareth, Gonzalez-Alcocer, Alfredo, Loera-Arias, Maria J., Saucedo-Cardenas, Odila, Montes de Oca-Luna, Roberto, Rodriguez-Rocha, Humberto, Garcia-Garcia, Aracely
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.12.2019; Springer Nature B.V
• Subjects: Animals; Apoptosis; Autophagy; Autophagy - drug effects; Autophagy - physiology; Biomedical and Life Sciences; Biomedicine; Calpain; Cell Biology; Cell death; Cell Death - drug effects; Cell Death - physiology; Cell Line, Tumor; Cognitive ability; Dopamine receptors; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Herbicides; Herbicides - toxicity; Humans; Male; Mesencephalon - drug effects; Mesencephalon - metabolism; Mice; Mice, Inbred C57BL; Mitochondria; Motor task performance; Movement disorders; Neurobiology; Neurodegenerative diseases; Neurology; Neurosciences; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - physiology; Paraquat; Paraquat - toxicity; Parkinson's disease; Phagocytosis; Phagosomes; Rapamycin; Oxidative stress; Paraquat; Rapamycin; Autophagy; Parkinson’s disease
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-019-01654-1

The neurodegenerative process of Parkinson’s disease (PD) involves autophagy impairment and oxidative stress. Therefore, we wanted to determine whether stimulation of autophagy protects dopaminergic cell death induced by oxidative stress in a PD model. Since environmental exposure to herbicides increases the risk to develop PD, the experimental model was established using the herbicide paraquat, which induces autophagy disruption, oxidative stress, and cell death. Rapamycin-stimulated autophagy inhibited calpain-dependent and independent apoptosis induced by paraquat. Autophagy stimulation decreased oxidative stress and peroxiredoxins (PRXs) hyperoxidation induced by paraquat. Cells exposed to paraquat displayed abnormally large autophagosomes enclosing mitochondria, which correlates with an increase of p62, an essential mitophagy regulator. Interestingly, when autophagy was stimulated before paraquat treatment, autophagosome size and number were similar to that observed in control cells. Motor and cognitive function impairment induced by paraquat showed an improvement when preceded by autophagy stimulation. Importantly, dopaminergic neuronal death and microglial activation mediated by paraquat were significantly reduced by rapamycin-induced autophagy. Our results indicate that autophagy stimulation has a protective effect on dopaminergic neurons and may have a promising potential to prevent or delay PD progression.