Autophagy Stimulation Decreases Dopaminergic Neuronal Death Mediated by Oxidative Stress


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.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7


  1. 1.

    Shults CW (2006) Lewy bodies. Proc Natl Acad Sci U S A 103(6):1661–1668.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Hornykiewicz O (2006) The discovery of dopamine deficiency in the parkinsonian brain. J Neural Transm Suppl (70):9–15

  3. 3.

    Horowitz MP, Greenamyre JT (2010) Gene-environment interactions in Parkinson’s disease: the importance of animal modeling. Clin Pharmacol Ther 88(4):467–474.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Vance JM, Ali S, Bradley WG, Singer C, Di Monte DA (2010) Gene-environment interactions in Parkinson’s disease and other forms of parkinsonism. Neurotoxicology 31 (5):598–602. doi:

  5. 5.

    Elbaz A, Tranchant C (2007) Epidemiologic studies of environmental exposures in Parkinson’s disease. J Neurol Sci 262(1–2):37–44.

    Article  PubMed  Google Scholar 

  6. 6.

    Franco R, Li S, Rodriguez-Rocha H, Burns M, Panayiotidis MI (2010) Molecular mechanisms of pesticide-induced neurotoxicity: Relevance to Parkinson’s disease. Chem Biol Interact 188(2):289–300.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Checkoway H, Nelson LM (1999) Epidemiologic approaches to the study of Parkinson’s disease etiology. Epidemiology 10(3):327–336

    CAS  Article  Google Scholar 

  8. 8.

    Tanner CM, Kamel F, Ross GW, Hoppin JA, Goldman SM, Korell M, Marras C, Bhudhikanok GS et al (2011) Rotenone, paraquat, and Parkinson’s disease. Environ Health Perspect 119(6):866–872.

  9. 9.

    Levy OA, Malagelada C, Greene LA (2009) Cell death pathways in Parkinson’s disease: proximal triggers, distal effectors, and final steps. Apoptosis 14(4):478–500.

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Bove J, Prou D, Perier C, Przedborski S (2005) Toxin-induced models of Parkinson’s disease. NeuroRx 2(3):484–494.

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Yao Z, Wood NW (2009) Cell death pathways in Parkinson’s disease: role of mitochondria. Antioxid Redox Signal 11(9):2135–2149.

  12. 12.

    Pollanen MS, Dickson DW, Bergeron C (1993) Pathology and biology of the Lewy body. J Neuropathol Exp Neurol 52(3):183–191

    CAS  Article  Google Scholar 

  13. 13.

    Cook C, Stetler C, Petrucelli L (2012) Disruption of protein quality control in Parkinson’s disease. Cold Spring Harb Perspect Med 2(5):a009423.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Ebrahimi-Fakhari D, Wahlster L, McLean PJ (2012) Protein degradation pathways in Parkinson’s disease: curse or blessing. Acta Neuropathol 124(2):153–172.

  15. 15.

    Mazzulli JR, Zunke F, Isacson O, Studer L, Krainc D (2016) α-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models. Proc Natl Acad Sci U S A 113(7):1931–1936.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC (2003) Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 278(27):25009–25013.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Dunn WA (1994) Autophagy and related mechanisms of lysosome-mediated protein degradation. Trends Cell Biol 4(4):139–143

    CAS  Article  Google Scholar 

  18. 18.

    Klionsky DJ, Emr SD (2000) Autophagy as a regulated pathway of cellular degradation. Science 290(5497):1717–1721

    CAS  Article  Google Scholar 

  19. 19.

    He C, Klionsky DJ (2009) Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43:67–93.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Eskelinen EL (2005) Maturation of autophagic vacuoles in mammalian cells. Autophagy 1(1):1–10

    CAS  Article  Google Scholar 

  21. 21.

    Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K et al (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441(7095):885–889.

  22. 22.

    Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M et al (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441(7095):880–884.

  23. 23.

    Friedman LG, Lachenmayer ML, Wang J, He L, Poulose SM, Komatsu M, Holstein GR, Yue Z (2012) Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of α-synuclein and LRRK2 in the brain. J Neurosci 32(22):7585–7593.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Ahmed I, Liang Y, Schools S, Dawson VL, Dawson TM, Savitt JM (2012) Development and characterization of a new Parkinson’s disease model resulting from impaired autophagy. J Neurosci 32(46):16503–16509.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Anglade P, Vyas S, Javoy-Agid F, Herrero MT, Michel PP, Marquez J, Mouatt-Prigent A, Ruberg M et al (1997) Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol 12(1):25–31

  26. 26.

    Zhu JH, Guo F, Shelburne J, Watkins S, Chu CT (2003) Localization of phosphorylated ERK/MAP kinases to mitochondria and autophagosomes in Lewy body diseases. Brain Pathol 13(4):473–481

    CAS  Article  Google Scholar 

  27. 27.

    Rodriguez-Rocha H, Garcia-Garcia A, Pickett C, Li S, Jones J, Chen H, Webb B, Choi J et al (2013) Compartmentalized oxidative stress in dopaminergic cell death induced by pesticides and complex I inhibitors: distinct roles of superoxide anion and superoxide dismutases. Free Radic Biol Med 61C:370–383.

  28. 28.

    Garcia-Garcia A, Anandhan A, Burns M, Chen H, Zhou Y, Franco R (2013) Impairment of Atg5-dependent autophagic flux promotes paraquat- and MPP+-induced apoptosis but not rotenone or 6-hydroxydopamine toxicity. Toxicol Sci 136(166):182.

    CAS  Article  Google Scholar 

  29. 29.

    González-Polo RA, Niso-Santano M, Ortíz-Ortíz MA, Gómez-Martín A, Morán JM, García-Rubio L, Francisco-Morcillo J, Zaragoza C et al (2007) Inhibition of paraquat-induced autophagy accelerates the apoptotic cell death in neuroblastoma SH-SY5Y cells. Toxicol Sci 97(2):448–458.

  30. 30.

    Wills J, Credle J, Oaks AW, Duka V, Lee JH, Jones J, Sidhu A (2012) Paraquat, but not maneb, induces synucleinopathy and tauopathy in striata of mice through inhibition of proteasomal and autophagic pathways. PLoS One 7(1):e30745.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z (2007) Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 26(7):1749–1760.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Kubota C, Torii S, Hou N, Saito N, Yoshimoto Y, Imai H, Takeuchi T (2010) Constitutive reactive oxygen species generation from autophagosome/lysosome in neuronal oxidative toxicity. J Biol Chem 285(1):667–674.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Chen Y, Azad MB, Gibson SB (2009) Superoxide is the major reactive oxygen species regulating autophagy. Cell Death Differ 16(7):1040–1052.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Wan FY, Wang YN, Zhang GJ (2001) The influence of oxidation of membrane thiol groups on lysosomal proton permeability. Biochem J 360(Pt 2):355–362

    CAS  Article  Google Scholar 

  35. 35.

    Bensaad K, Cheung EC, Vousden KH (2009) Modulation of intracellular ROS levels by TIGAR controls autophagy. EMBO J 28(19):3015–3026.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Jung CH, Ro SH, Cao J, Otto NM, Kim DH (2010) mTOR regulation of autophagy. FEBS Lett 584(7):1287–1295.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Noda T, Ohsumi Y (1998) Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem 273(7):3963–3966

    CAS  Article  Google Scholar 

  38. 38.

    Fei Q, McCormack AL, Di Monte DA, Ethell DW (2008) Paraquat neurotoxicity is mediated by a Bak-dependent mechanism. J Biol Chem 283(6):3357–3364.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Yang W, Tiffany-Castiglioni E, Koh HC, Son IH (2009) Paraquat activates the IRE1/ASK1/JNK cascade associated with apoptosis in human neuroblastoma SH-SY5Y cells. Toxicol Lett 191 (2–3):203–210. doi:

  40. 40.

    Nuber S, Tadros D, Fields J, Overk CR, Ettle B, Kosberg K, Mante M, Rockenstein E et al (2014) Environmental neurotoxic challenge of conditional alpha-synuclein transgenic mice predicts a dopaminergic olfactory-striatal interplay in early PD. Acta Neuropathol 127(4):477–494.

  41. 41.

    Suzuki J, Denning DP, Imanishi E, Horvitz HR, Nagata S (2013) Xk-related protein 8 and CED-8 promote phosphatidylserine exposure in apoptotic cells. Science 341(6144):403–406.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Suzuki J, Imanishi E, Nagata S (2014) Exposure of phosphatidylserine by Xk-related protein family members during apoptosis. J Biol Chem 289(44):30257–30267.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Suzuki J, Imanishi E, Nagata S (2016) Xkr8 phospholipid scrambling complex in apoptotic phosphatidylserine exposure. Proc Natl Acad Sci U S A 113(34):9509–9514.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Rhee SG, Woo HA (2011) Multiple functions of peroxiredoxins: peroxidases, sensors and regulators of the intracellular messenger H2O2, and protein chaperones. Antioxid Redox Signal 15(3):781–794.

  45. 45.

    Bryk R, Griffin P, Nathan C (2000) Peroxynitrite reductase activity of bacterial peroxiredoxins. Nature 407(6801):211–215.

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Rhee SG, Woo HA, Kil IS, Bae SH (2012) Peroxiredoxin functions as a peroxidase and a regulator and sensor of local peroxides. J Biol Chem 287(7):4403–4410.

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Lei S, Zavala-Flores L, Garcia-Garcia A, Nandakumar R, Huang Y, Madayiputhiya N, Stanton RC, Dodds ED et al (2014) Alterations in energy/redox metabolism induced by mitochondrial and environmental toxins: a specific role for glucose-6-phosphate-dehydrogenase and the pentose phosphate pathway in paraquat toxicity. ACS Chem Biol 9(9):2032–2048.

  48. 48.

    Lee YM, Park SH, Shin DI, Hwang JY, Park B, Park YJ, Lee TH, Chae HZ et al (2008) Oxidative modification of peroxiredoxin is associated with drug-induced apoptotic signaling in experimental models of Parkinson disease. J Biol Chem 283(15):9986–9998.

  49. 49.

    Roede JR, Hansen JM, Go YM, Jones DP (2011) Maneb and paraquat-mediated neurotoxicity: involvement of peroxiredoxin/thioredoxin system. Toxicol Sci 121(2):368–375.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Woo HA, Kang SW, Kim HK, Yang KS, Chae HZ, Rhee SG (2003) Reversible oxidation of the active site cysteine of peroxiredoxins to cysteine sulfinic acid. Immunoblot detection with antibodies specific for the hyperoxidized cysteine-containing sequence. J Biol Chem 278(48):47361–47364.

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Eskelinen EL (2008) Fine structure of the autophagosome. Methods Mol Biol 445:11–28.

    Article  PubMed  Google Scholar 

  52. 52.

    Loos B, du Toit A, Hofmeyr JH (2014) Defining and measuring autophagosome flux—Concept and reality. Autophagy 10(11):2087–2096.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Poole B, Ohkuma S (1981) Effect of weak bases on the intralysosomal pH in mouse peritoneal macrophages. J Cell Biol 90(3):665–669

    CAS  Article  Google Scholar 

  54. 54.

    Glaumann H, Ahlberg J (1987) Comparison of different autophagic vacuoles with regard to ultrastructure, enzymatic composition, and degradation capacity--formation of crinosomes. Exp Mol Pathol 47(3):346–362

    CAS  Article  Google Scholar 

  55. 55.

    Liu H, Dai C, Fan Y, Guo B, Ren K, Sun T, Wang W (2017) From autophagy to mitophagy: the roles of P62 in neurodegenerative diseases. J Bioenerg Biomembr 49(5):413–422.

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    Jankovic J (2008) Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 79(4):368–376.

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Bloem BR, Hausdorff JM, Visser JE, Giladi N (2004) Falls and freezing of gait in Parkinson’s disease: a review of two interconnected, episodic phenomena. Mov Disord 19(8):871–884.

    Article  PubMed  Google Scholar 

  58. 58.

    Giladi N, Treves TA, Simon ES, Shabtai H, Orlov Y, Kandinov B, Paleacu D, Korczyn AD (2001) Freezing of gait in patients with advanced Parkinson’s disease. J Neural Transm (Vienna) 108(1):53–61.

    CAS  Article  Google Scholar 

  59. 59.

    Sager TN, Kirchhoff J, Mørk A, Van Beek J, Thirstrup K, Didriksen M, Lauridsen JB (2010) Nest building performance following MPTP toxicity in mice. Behav Brain Res 208(2):444–449.

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Deacon RM (2006) Assessing nest building in mice. Nat Protoc 1(3):1117–1119.

    Article  PubMed  Google Scholar 

  61. 61.

    Hess SE, Rohr S, Dufour BD, Gaskill BN, Pajor EA, Garner JP (2008) Home improvement: C57BL/6J mice given more naturalistic nesting materials build better nests. J Am Assoc Lab Anim Sci 47(6):25–31

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    McGeer PL, McGeer EG (2008) Glial reactions in Parkinson’s disease. Mov Disord 23(4):474–483.

    Article  PubMed  Google Scholar 

  63. 63.

    Purisai MG, McCormack AL, Cumine S, Li J, Isla MZ, Di Monte DA (2007) Microglial activation as a priming event leading to paraquat-induced dopaminergic cell degeneration. Neurobiol Dis 25(2):392–400.

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Cicchetti F, Lapointe N, Roberge-Tremblay A, Saint-Pierre M, Jimenez L, Ficke BW, Gross RE (2005) Systemic exposure to paraquat and maneb models early Parkinson’s disease in young adult rats. Neurobiol Dis 20(2):360–371.

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Dong X, Milholland B, Vijg J (2016) Evidence for a limit to human lifespan. Nature 538(7624):257–259.

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Arduíno DM, Esteves AR, Cortes L, Silva DF, Patel B, Grazina M, Swerdlow RH, Oliveira CR et al (2012) Mitochondrial metabolism in Parkinson’s disease impairs quality control autophagy by hampering microtubule-dependent traffic. Hum Mol Genet 21(21):4680–4702.

  67. 67.

    Radad K, Moldzio R, Rausch WD (2015) Rapamycin protects dopaminergic neurons against rotenone-induced cell death in primary mesencephalic cell culture. Folia Neuropathol 53(3):250–261

    Article  Google Scholar 

  68. 68.

    Pan T, Rawal P, Wu Y, Xie W, Jankovic J, Le W (2009) Rapamycin protects against rotenone-induced apoptosis through autophagy induction. Neuroscience 164(2):541–551.

    CAS  Article  PubMed  Google Scholar 

  69. 69.

    Mouatt-Prigent A, Karlsson JO, Agid Y, Hirsch EC (1996) Increased M-calpain expression in the mesencephalon of patients with Parkinson’s disease but not in other neurodegenerative disorders involving the mesencephalon: a role in nerve cell death? Neuroscience 73(4):979–987

    CAS  Article  Google Scholar 

  70. 70.

    Crocker SJ, Smith PD, Jackson-Lewis V, Lamba WR, Hayley SP, Grimm E, Callaghan SM, Slack RS et al (2003) Inhibition of calpains prevents neuronal and behavioral deficits in an MPTP mouse model of Parkinson’s disease. J Neurosci 23(10):4081–4091

  71. 71.

    Samantaray S, Butler JT, Ray SK, Banik NL (2008) Extranigral neurodegeneration in Parkinson’s disease. Ann N Y Acad Sci 1139:331–336.

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Esteves AR, Arduíno DM, Swerdlow RH, Oliveira CR, Cardoso SM (2010) Dysfunctional mitochondria uphold calpain activation: Contribution to Parkinson’s disease pathology. Neurobiol Dis 37(3):723–730.

    CAS  Article  PubMed  Google Scholar 

  73. 73.

    Jiang J, Zuo Y, Gu Z (2013) Rapamycin protects the mitochondria against oxidative stress and apoptosis in a rat model of Parkinson’s disease. Int J Mol Med 31(4):825–832.

    CAS  Article  PubMed  Google Scholar 

  74. 74.

    Das A, Durrant D, Koka S, Salloum FN, Xi L, Kukreja RC (2014) Mammalian target of rapamycin (mTOR) inhibition with rapamycin improves cardiac function in type 2 diabetic mice: potential role of attenuated oxidative stress and altered contractile protein expression. J Biol Chem 289(7):4145–4160.

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Sun DZ, Song CQ, Xu YM, Wang R, Liu W, Liu Z, Dong XS (2018) Involvement of PINK1/Parkin-mediated mitophagy in paraquat- induced apoptosis in human lung epithelial-like A549 cells. Toxicol in Vitro 53:148–159.

    CAS  Article  PubMed  Google Scholar 

  76. 76.

    Brooks AI, Chadwick CA, Gelbard HA, Cory-Slechta DA, Federoff HJ (1999) Paraquat elicited neurobehavioral syndrome caused by dopaminergic neuron loss. Brain Res 823(1–2):1–10

    CAS  Article  Google Scholar 

  77. 77.

    Majumder S, Richardson A, Strong R, Oddo S (2011) Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits. PLoS One 6(9):e25416.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Thiruchelvam M, Richfield EK, Baggs RB, Tank AW, Cory-Slechta DA (2000) The nigrostriatal dopaminergic system as a preferential target of repeated exposures to combined paraquat and maneb: implications for Parkinson’s disease. J Neurosci 20(24):9207–9214

    CAS  Article  Google Scholar 

  79. 79.

    Peng J, Mao XO, Stevenson FF, Hsu M, Andersen JK (2004) The herbicide paraquat induces dopaminergic nigral apoptosis through sustained activation of the JNK pathway. J Biol Chem 279(31):32626–32632.

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    McCormack AL, Thiruchelvam M, Manning-Bog AB, Thiffault C, Langston JW, Cory-Slechta DA, Di Monte DA (2002) Environmental risk factors and Parkinson’s disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol Dis 10(2):119–127

    CAS  Article  Google Scholar 

  81. 81.

    Malagelada C, Jin ZH, Jackson-Lewis V, Przedborski S, Greene LA (2010) Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson’s disease. J Neurosci 30(3):1166–1175.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Liu K, Shi N, Sun Y, Zhang T, Sun X (2013) Therapeutic effects of rapamycin on MPTP-induced parkinsonism in mice. Neurochem Res 38(1):201–207.

    CAS  Article  PubMed  Google Scholar 

  83. 83.

    McGeer PL, Schwab C, Parent A, Doudet D (2003) Presence of reactive microglia in monkey substantia nigra years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. Ann Neurol 54(5):599–604.

    CAS  Article  PubMed  Google Scholar 

  84. 84.

    Barcia C, Sánchez Bahillo A, Fernández-Villalba E, Bautista V, Poza Y, Poza M, Fernández-Barreiro A, Hirsch EC et al (2004) Evidence of active microglia in substantia nigra pars compacta of parkinsonian monkeys 1 year after MPTP exposure. Glia 46(4):402–409.

  85. 85.

    Sugama S, Yang L, Cho BP, DeGiorgio LA, Lorenzl S, Albers DS, Beal MF, Volpe BT et al (2003) Age-related microglial activation in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration in C57BL/6 mice. Brain Res 964(2):288–294

  86. 86.

    Cicchetti F, Brownell AL, Williams K, Chen YI, Livni E, Isacson O (2002) Neuroinflammation of the nigrostriatal pathway during progressive 6-OHDA dopamine degeneration in rats monitored by immunohistochemistry and PET imaging. Eur J Neurosci 15(6):991–998

    CAS  Article  Google Scholar 

  87. 87.

    Depino AM, Earl C, Kaczmarczyk E, Ferrari C, Besedovsky H, del Rey A, Pitossi FJ, Oertel WH (2003) Microglial activation with atypical proinflammatory cytokine expression in a rat model of Parkinson’s disease. Eur J Neurosci 18(10):2731–2742

    Article  Google Scholar 

  88. 88.

    Sherer TB, Betarbet R, Kim JH, Greenamyre JT (2003) Selective microglial activation in the rat rotenone model of Parkinson’s disease. Neurosci Lett 341(2):87–90

    CAS  Article  Google Scholar 

  89. 89.

    Lu M, Su C, Qiao C, Bian Y, Ding J, Hu G (2016) Metformin prevents dopaminergic neuron death in MPTP/P-induced mouse model of Parkinson’s disease via autophagy and mitochondrial ROS clearance. Int J Neuropsychopharmacol 19(9):pyw047.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Kirchhoff J, Mørk A, Brennum LT, Sager TN (2009) Striatal extracellular dopamine levels and behavioural reversal in MPTP-lesioned mice. Neuroreport 20(5):482–486.

    Article  PubMed  Google Scholar 

Download references


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.

Author information



Corresponding author

Correspondence to Aracely Garcia-Garcia.

Ethics declarations

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.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material


(PPTX 67572 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation


  • Autophagy
  • Oxidative stress
  • Paraquat
  • Parkinson’s disease
  • Rapamycin