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Autophagy Stimulation Decreases Dopaminergic Neuronal Death Mediated by Oxidative Stress

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Abstract

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.

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Acknowledgments

This work was supported by the National Council of Science and Technology (Consejo Nacional de Ciencia y Tecnología, CONACYT: CB-2013-221615) and the Program for the Professional Development of the Professors (Programa para el Desarrollo Profesional Docente, PRODEP) (DSA/103.5/14/11021) to AGG. MJRM, APDJ, YGC, and AGA received a scholarship from CONACYT.

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Authors and Affiliations

  1. Departamento de Histologia, Facultad de Medicina, Universidad Autonoma de Nuevo Leon, Francisco I. Madero S/N, 64460, Monterrey, Nuevo Leon, Mexico

    Marcela J. Ramirez-Moreno, Ana P. Duarte-Jurado, Yareth Gopar-Cuevas, Alfredo Gonzalez-Alcocer, Maria J. Loera-Arias, Odila Saucedo-Cardenas, Roberto Montes de Oca-Luna, Humberto Rodriguez-Rocha & Aracely Garcia-Garcia

  2. Departamento de Genética Molecular, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Delegación Nuevo León, , Mexico

    Odila Saucedo-Cardenas

Authors
  1. Marcela J. Ramirez-Moreno
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  2. Ana P. Duarte-Jurado
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  3. Yareth Gopar-Cuevas
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  4. Alfredo Gonzalez-Alcocer
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  5. Maria J. Loera-Arias
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  6. Odila Saucedo-Cardenas
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  7. Roberto Montes de Oca-Luna
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  8. Humberto Rodriguez-Rocha
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  9. Aracely Garcia-Garcia
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Corresponding author

Correspondence to Aracely Garcia-Garcia.

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Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving animals were following the Mexican Official Norm “NOM-062-ZOO-1999” (De Aluja, 2002) and our university’s Institutional Animal Care and Use Committee (Comite Institucional para el Cuidado y Uso de los Animales de Laboratorio, CICUAL). This study was approved by the Ethical Committee of our University (registration number HT17-00004).

Author Contributions

HRR and AGG conceived and designed the experiments. APDJ performed the experiments of cell death and oxidative stress. YGC performed the analyses of flow cytometry and TEM. MJRM and AGA performed the experiments in mice. MJRM, APDJ, YGC, AGA, MJLA, OSC, RMOL, HRR, and AGG analyzed the results. MJLA, OSC, RMOL, and HRR provided feedback on the manuscript. MJRM and AGG wrote the paper. All the authors reviewed and approved the final version of the manuscript.

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Ramirez-Moreno, M.J., Duarte-Jurado, A.P., Gopar-Cuevas, Y. et al. Autophagy Stimulation Decreases Dopaminergic Neuronal Death Mediated by Oxidative Stress. Mol Neurobiol 56, 8136–8156 (2019). https://doi.org/10.1007/s12035-019-01654-1

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