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Agrochemicals-Induced Dopaminergic Neurotoxicity: Role of Mitochondria-Mediated Oxidative Stress and Protein Clearance Mechanisms

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Toxicity and Autophagy in Neurodegenerative Disorders

Part of the book series: Current Topics in Neurotoxicity ((Current Topics Neurotoxicity,volume 9))

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Abstract

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder that is characterized by the progressive loss of substantia nigral dopaminergic neurons resulting in the pronounced depletion of striatal DA levels which subsequently leads to the expression of cardinal features of PD including tremor, bradykinesia, rigidity and postural instability. The mechanisms underlying the selective loss of dopaminergic neurons remain poorly understood; however, studies conducted in post mortem PD brains and experimental PD models have implicated oxidative stress and mitochondrial dysfunction in the mechanism of dopaminergic neurodegeneration. In recent years, the etiology of several neurodegenerative diseases including PD has been linked to low dose and chronic exposure to a variety of agrochemicals including paraquat, rotenone and dieldrin. Here we discuss how several of these pesticides share common mechanistic events, including oxidative stress, mitochondrial impairment/complex I inhibition, abnormal protein aggregation and post translational modifications (PTMs) of proteins including α-synuclein, as well as dopaminergic cell death. Furthermore, intersecting and parallel effects of environmental neurotoxicants on protein clearance mechanisms and mitochondrial function are addressed and hence provide novel insights that might be beneficial in the development of targeted therapies for PD.

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Abbreviations

ALP:

autophagolysosomal pathway

ARE:

antioxidant response element

ASK1:

apoptosis signal kinase 1

ATG:

autophagy related gene

AV:

autophagic vacuoles

BBB:

blood-brain barrier

CI:

confidence interval

CMA:

chaperone-mediated autophagy

CNS:

central nervous system

COX:

cycloxygenase

DA:

dopamine

DAT:

dopamine transporter

L-DOPA:

L-3,4-dihydroxyphenylalanine

ENS:

enteric neuron system

ER:

endoplasmic reticulum

ETC:

electron transfer chain modification

GSK-3β:

glycogen synthase kinase-3 beta

GSTT1:

glutathione-S-transferase theta 1

HIF:

hypoxia inducible factor

4-HNE:

4-hydroxynonenal

HSC:

heat shock conjugate

LAMP2:

lysosome-associated membrane protein type-2

LB:

Lewy body

LC3:

Microtubule associated protein Light Chain 3

LRRK2:

leucine-rich repeat kinase 2

LUHMES:

Lund human mesencephalic

3-MA:

3-methyladenine

MA:

methamphetamine

MPTP:

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

mTOR:

mammalian target of rapamycin

NDl1:

N-MYC downregulated-like 1

Ndufs4:

NADH dehydrogenase (ubiquinone) Fe-S protein 4

NOX:

NADPH oxidase

OR:

odds ratio

PD:

Parkinson’s Disease

PINK-1:

PTEN-induced putative kinase 1

PKC:

protein Kinase C delta

PQ:

paraquat

PTM:

posttranslational UCH-L1: ubiquitin carboxyl terminal hydrolase isoenzyme L1

PTEN:

phosphatase and tensin homolog

POLG:

polymerase gamma

RNS:

reactive nitrogen species

ROS:

reactive oxygen species

SCF:

SKP1-Cullin1-F-box

SKP1:

s-phase kinase-associated protein 1

SN:

substantia nigra

TFAM:

mitochondrial transcription factor A

UPS:

ubiquitin proteasomal system

VMAT2:

vesicular monoamine transporter

WT:

wild-type

References

  1. Dexter DT, Jenner P. Parkinson disease: from pathology to molecular disease mechanisms. Free Radic Biol Med. 2013;62:132–44 (PubMed PMID: 23380027).

    CAS  PubMed  Google Scholar 

  2. Braak H, Braak E. Pathoanatomy of Parkinson’s disease. J Neurol. 2000;247(Suppl 2):II3–10 (PubMed PMID: 10991663).

    PubMed  Google Scholar 

  3. Dick FD, De Palma G, Ahmadi A, Scott NW, Prescott GJ, Bennett J, et al. Environmental risk factors for Parkinson’s disease and parkinsonism: the Geoparkinson study. Occup Environ Med. 2007;64(10):666–72 (PubMed PMID: 17332139. Pubmed Central PMCID: 2078401).

    PubMed Central  CAS  PubMed  Google Scholar 

  4. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature. 1997;388(6645):839–40 (PubMed PMID: 9278044).

    CAS  PubMed  Google Scholar 

  5. Licker V, Kovari E, Hochstrasser DF, Burkhard PR. Proteomics in human Parkinson’s disease research. J Proteomics. 2009;73(1):10–29 (PubMed PMID: 19632367).

    CAS  PubMed  Google Scholar 

  6. Venda LL, Cragg SJ, Buchman VL, Wade-Martins R. α-Synuclein and dopamine at the crossroads of Parkinson’s disease. Trends Neurosci. 2010;33(12):559–68 (PubMed PMID: 20961626. Pubmed Central PMCID: 3631137).

    PubMed Central  CAS  PubMed  Google Scholar 

  7. Ubhi K, Low P, Masliah E. Multiple system atrophy: a clinical and neuropathological perspective. Trends Neurosci. 2011;34(11):581–90 (PubMed PMID: 21962754. Pubmed Central PMCID: 3200496).

    PubMed Central  CAS  PubMed  Google Scholar 

  8. Wood-Kaczmar A, Gandhi S, Wood NW. Understanding the molecular causes of Parkinson’s disease. Trends Mol Med. 2006;12(11):521–8 (PubMed PMID: 17027339).

    CAS  PubMed  Google Scholar 

  9. Coppede F, Mancuso M, Siciliano G, Migliore L, Murri L. Genes and the environment in neurodegeneration. Biosci Rep. 2006;26(5):341–67 (PubMed PMID: 17029001).

    CAS  PubMed  Google Scholar 

  10. Thomas B, Beal MF. Parkinson’s disease. Hum Mol Genet. 2007;16(Spec No. 2):R183–94 (PubMed PMID: 17911161).

    CAS  PubMed  Google Scholar 

  11. Baltazar MT, Dinis-Oliveira RJ, de Lourdes Bastos M, Tsatsakis AM, Duarte JA, Carvalho F. Pesticides exposure as etiological factors of Parkinson’s disease and other neurodegenerative diseases—a mechanistic approach. Toxicol Lett. 2014;230:85–103 (PubMed PMID: 24503016).

    CAS  PubMed  Google Scholar 

  12. Davie CA. A review of Parkinson’s disease. British Med Bull. 2008;86:109–27 (PubMed PMID: 18398010).

    CAS  Google Scholar 

  13. Foltynie T, Brayne C, Barker RA. The heterogeneity of idiopathic Parkinson’s disease. J Neurol. 2002;249(2):138–45 (PubMed PMID: 11985378).

    PubMed  Google Scholar 

  14. Foltynie T, Sawcer S, Brayne C, Barker RA. The genetic basis of Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2002;73(4):363–70 (PubMed PMID: 12235301. Pubmed Central PMCID: 1738059).

    PubMed Central  CAS  PubMed  Google Scholar 

  15. Gorell JM, Peterson EL, Rybicki BA, Johnson CC. Multiple risk factors for Parkinson’s disease. J Neurol Sci. 2004;217(2):169–74 (PubMed PMID: 14706220).

    PubMed  Google Scholar 

  16. Hancock DB, Martin ER, Mayhew GM, Stajich JM, Jewett R, Stacy MA, et al. Pesticide exposure and risk of Parkinson’s disease: a family-based case-control study. BMC Neurol. 2008;8:6 (PubMed PMID: 18373838. Pubmed Central PMCID: 2323015).

    PubMed Central  PubMed  Google Scholar 

  17. Tufekci KU, Meuwissen R, Genc S, Genc K. Inflammation in Parkinson’s disease. Adv Protein Chem Struct Biol. 2012;88:69–132 (PubMed PMID: 22814707).

    CAS  PubMed  Google Scholar 

  18. Androutsopoulos VP, Kanavouras K, Tsatsakis AM. Role of paraoxonase 1 (PON1) in organophosphate metabolism: implications in neurodegenerative diseases. Toxicol Appl Pharmacol. 2011;256(3):418–24 (PubMed PMID: 21864557).

    CAS  PubMed  Google Scholar 

  19. Freire C, Koifman S. Pesticide exposure and Parkinson’s disease: epidemiological evidence of association. Neurotoxicology. 2012;33(5):947–71 (PubMed PMID: 22627180).

    CAS  PubMed  Google Scholar 

  20. Tanner CM. Advances in environmental epidemiology. Mov Disord. 2010;25(Suppl 1):S58–62 (PubMed PMID: 20187243).

    PubMed  Google Scholar 

  21. Rugbjerg K, Harris MA, Shen H, Marion SA, Tsui JK, Teschke K. Pesticide exposure and risk of Parkinson’s disease—a population-based case-control study evaluating the potential for recall bias. Scand J Work Environ Health. 2011;37(5):427–36 (PubMed PMID: 21240453).

    CAS  PubMed  Google Scholar 

  22. Vlajinac HD, Sipetic SB, Maksimovic JM, Marinkovic JM, Dzoljic ED, Ratkov IS, et al. Environmental factors and Parkinson’s disease: a case-control study in Belgrade, Serbia. Int J Neurosci. 2010;120(5):361–7 (PubMed PMID: 20402575).

    PubMed  Google Scholar 

  23. Weisskopf MG, Knekt P, O’Reilly EJ, Lyytinen J, Reunanen A, Laden F, et al. Persistent organochlorine pesticides in serum and risk of Parkinson disease. Neurol. 2010;74(13):1055–61 (PubMed PMID: 20350979. Pubmed Central PMCID: 2848105).

    CAS  Google Scholar 

  24. Brown TP, Rumsby PC, Capleton AC, Rushton L, Levy LS. Pesticides and Parkinson’s disease—is there a link? Environ Health Perspect. 2006;114(2):156–64 (PubMed PMID: 16451848. Pubmed Central PMCID: 1367825).

    PubMed Central  PubMed  Google Scholar 

  25. Behari M, Srivastava AK, Das RR, Pandey RM. Risk factors of Parkinson’s disease in Indian patients. J Neurol Sci. 2001;190(1–2):49–55 (PubMed PMID: 11574106).

    CAS  PubMed  Google Scholar 

  26. Firestone JA, Lundin JI, Powers KM, Smith-Weller T, Franklin GM, Swanson PD, et al. Occupational factors and risk of Parkinson’s disease: a population-based case-control study. Am J Ind Med. 2010;53(3):217–23 (PubMed PMID: 20025075. Pubmed Central PMCID: 3299410).

    PubMed Central  PubMed  Google Scholar 

  27. Priyadarshi A, Khuder SA, Schaub EA, Shrivastava S. A meta-analysis of Parkinson’s disease and exposure to pesticides. Neurotoxicology. 2000;21(4):435–40 (PubMed PMID: 11022853).

    CAS  PubMed  Google Scholar 

  28. Cannon JR, Greenamyre JT. The role of environmental exposures in neurodegeneration and neurodegenerative diseases. Toxicol Sci. 2011;124(2):225–50 (PubMed PMID: 21914720. Pubmed Central PMCID: 3216414).

    PubMed Central  CAS  PubMed  Google Scholar 

  29. Bove J, Prou D, Perier C, Przedborski S. Toxin-induced models of Parkinson’s disease. NeuroRx. 2005;2(3):484–94 (PubMed PMID: 16389312. Pubmed Central PMCID: 1144492).

    PubMed Central  PubMed  Google Scholar 

  30. Langston JW, Ballard PA, Jr. Parkinson’s disease in a chemist working with 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. N Engl J Med. 1983;309(5):310 (PubMed PMID: 6602944).

    CAS  PubMed  Google Scholar 

  31. Richardson JR, Caudle WM, Guillot TS, Watson JL, Nakamaru-Ogiso E, Seo BB, et al. Obligatory role for complex I inhibition in the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Toxicol Sci. 2007;95(1):196–204 (PubMed PMID: 17038483).

    CAS  PubMed  Google Scholar 

  32. Exner N, Lutz AK, Haass C, Winklhofer KF. Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. EMBO J. 2012;31(14):3038–62 (PubMed PMID: 22735187. Pubmed Central PMCID: 3400019).

    PubMed Central  CAS  PubMed  Google Scholar 

  33. Moretto A, Colosio C. Biochemical and toxicological evidence of neurological effects of pesticides: the example of Parkinson’s disease. Neurotoxicology. 2011;32(4):383–91 (PubMed PMID: 21402100).

    CAS  PubMed  Google Scholar 

  34. Franco R, Li S, Rodriguez-Rocha H, Burns M, Panayiotidis MI. Molecular mechanisms of pesticide-induced neurotoxicity: relevance to Parkinson’s disease. Chem Biol Interact. 2010;188(2):289–300 (PubMed PMID: 20542017. Pubmed Central PMCID: 2942983).

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Ghosh A, Chandran K, Kalivendi SV, Joseph J, Antholine WE, Hillard CJ, et al. Neuroprotection by a mitochondria-targeted drug in a Parkinson’s disease model. Free Radic Biol Med. 2010;49(11):1674–84 (PubMed PMID: 20828611. Pubmed Central PMCID: 4020411).

    PubMed Central  CAS  PubMed  Google Scholar 

  36. Jin H, Kanthasamy A, Ghosh A, Anantharam V, Kalyanaraman B, Kanthasamy AG. Mitochondria-targeted antioxidants for treatment of Parkinson’s disease: preclinical and clinical outcomes. Biochim Biophys Acta. 2014;1842(8):1282–94 (PubMed PMID: 24060637. Pubmed Central PMCID: 3961561).

    CAS  PubMed  Google Scholar 

  37. Lin M, Chandramani-Shivalingappa P, Jin H, Ghosh A, Anantharam V, Ali S, et al. Methamphetamine-induced neurotoxicity linked to ubiquitin-proteasome system dysfunction and autophagy-related changes that can be modulated by protein kinase C delta in dopaminergic neuronal cells. Neuroscience. 2012;210:308–32 (PubMed PMID: 22445524. Pubmed Central PMCID: 3358550).

    PubMed Central  CAS  PubMed  Google Scholar 

  38. Shen YF, Tang Y, Zhang XJ, Huang KX, Le WD. Adaptive changes in autophagy after UPS impairment in Parkinson’s disease. Acta Pharmacol Sin. 2013;34(5):667–73 (PubMed PMID: 23503475).

    PubMed Central  CAS  PubMed  Google Scholar 

  39. Simon-Sanchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, et al. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet. 2009;41(12):1308–12 (PubMed PMID: 19915575. Pubmed Central PMCID: 2787725).

    PubMed Central  CAS  PubMed  Google Scholar 

  40. Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD. Mitochondrial complex I deficiency in Parkinson’s disease. J Neurochem. 1990;54(3):823–7 (PubMed PMID: 2154550).

    CAS  PubMed  Google Scholar 

  41. Coskun P, Wyrembak J, Schriner SE, Chen HW, Marciniack C, Laferla F, et al. A mitochondrial etiology of Alzheimer and Parkinson disease. Biochim Biophys Acta. 2012;1820(5):553–64 (PubMed PMID: 21871538. Pubmed Central PMCID: 3270155).

    PubMed Central  CAS  PubMed  Google Scholar 

  42. Hauser DN, Hastings TG. Mitochondrial dysfunction and oxidative stress in Parkinson’s disease and monogenic parkinsonism. Neurobiol Dis. 2013;51:35–42 (PubMed PMID: 23064436. Pubmed Central PMCID: 3565564).

    PubMed Central  CAS  PubMed  Google Scholar 

  43. Celardo I, Martins LM, Gandhi S. Unravelling mitochondrial pathways to Parkinson’s disease. Br J Pharmacol. 2014;171(8):1943–57 (PubMed PMID: 24117181. Pubmed Central PMCID: 3976614).

    PubMed Central  CAS  PubMed  Google Scholar 

  44. Green DR, Galluzzi L, Kroemer G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science. 2011;333(6046):1109–12 (PubMed PMID: WOS:000294244300037. English).

    PubMed Central  CAS  PubMed  Google Scholar 

  45. Shin JY, Park HJ, Ahn YH, Lee PH. Neuroprotective effect of L-dopa on dopaminergic neurons is comparable to pramipexol in MPTP-treated animal model of Parkinson’s disease: a direct comparison study. J Neurochem. 2009;111(4):1042–50 (PubMed PMID: 19765187).

    CAS  PubMed  Google Scholar 

  46. Ogawa N, Asanuma M, Miyazaki I, Diaz-Corrales FJ, Miyoshi K. L-DOPA treatment from the viewpoint of neuroprotection. Possible mechanism of specific and progressive dopaminergic neuronal death in Parkinson’s disease. J Neurol. 2005;252(Suppl 4):IV23–31 (PubMed PMID: 16222434).

    PubMed  Google Scholar 

  47. Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci. 2000;3(12):1301–6 (PubMed PMID: 11100151).

    CAS  PubMed  Google Scholar 

  48. Hattori N, Tanaka M, Ozawa T, Mizuno Y. Immunohistochemical studies on complexes I, II, III, and IV of mitochondria in Parkinson’s disease. Ann Neurol. 1991;30(4):563–71 (PubMed PMID: 1665052).

    CAS  PubMed  Google Scholar 

  49. Mizuno Y, Ohta S, Tanaka M, Takamiya S, Suzuki K, Sato T, et al. Deficiencies in complex I subunits of the respiratory chain in Parkinson’s disease. Biochem Biophys Res Commun. 1989;163(3):1450–5 (PubMed PMID: 2551290).

    CAS  PubMed  Google Scholar 

  50. Mytilineou C, Werner P, Molinari S, Di Rocco A, Cohen G, Yahr MD. Impaired oxidative decarboxylation of pyruvate in fibroblasts from patients with Parkinson’s disease. J Neural Transm Park Dis Dement Sect. 1994;8(3):223–8 (PubMed PMID: 7748465).

    CAS  PubMed  Google Scholar 

  51. Blin O, Desnuelle C, Rascol O, Borg M, Peyro Saint Paul H, Azulay JP, et al. Mitochondrial respiratory failure in skeletal muscle from patients with Parkinson’s disease and multiple system atrophy. J Neurol Sci. 1994;125(1):95–101 (PubMed PMID: 7964895).

    CAS  PubMed  Google Scholar 

  52. Haas RH, Nasirian F, Nakano K, Ward D, Pay M, Hill R, et al. Low platelet mitochondrial complex I and complex II/III activity in early untreated Parkinson’s disease. Ann Neurol. 1995;37(6):714–22 (PubMed PMID: 7778844).

    CAS  PubMed  Google Scholar 

  53. Swerdlow RH. Mitochondria in cybrids containing mtDNA from persons with mitochondriopathies. J Neurosci Res. 2007;85(15):3416–28 (PubMed PMID: 17243174).

    CAS  PubMed  Google Scholar 

  54. Drechsel DA, Patel M. Role of reactive oxygen species in the neurotoxicity of environmental agents implicated in Parkinson’s disease. Free Radic Biol Med. 2008;44(11):1873–86 (PubMed PMID: 18342017. Pubmed Central PMCID: 2723777).

    PubMed Central  CAS  PubMed  Google Scholar 

  55. Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 2006;443(7113):787–95 (PubMed PMID: 17051205).

    CAS  PubMed  Google Scholar 

  56. Schapira AH. Mitochondrial dysfunction in Parkinson’s disease. Cell Death Differ. 2007;14(7):1261–6 (PubMed PMID: 17464321).

    CAS  PubMed  Google Scholar 

  57. Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet. 2006;38(5):515–7 (PubMed PMID: 16604074).

    CAS  PubMed  Google Scholar 

  58. Guo X, Kudryavtseva E, Bodyak N, Nicholas A, Dombrovsky I, Yang D, et al. Mitochondrial DNA deletions in mice in men: substantia nigra is much less affected in the mouse. Biochim Biophys Acta. 2010;1797(6–7):1159–62 (PubMed PMID: 20388490. Pubmed Central PMCID: 2891141).

    PubMed Central  CAS  PubMed  Google Scholar 

  59. Reeve A, Meagher M, Lax N, Simcox E, Hepplewhite P, Jaros E, et al. The impact of pathogenic mitochondrial DNA mutations on substantia nigra neurons. J Neurosci. 2013;33(26):10790–801 (PubMed PMID: 23804100).

    CAS  PubMed  Google Scholar 

  60. Ekstrand MI, Falkenberg M, Rantanen A, Park CB, Gaspari M, Hultenby K, et al. Mitochondrial transcription factor A regulates mtDNA copy number in mammals. Hum Mol Genet. 2004;13(9):935–44 (PubMed PMID: 15016765).

    CAS  PubMed  Google Scholar 

  61. Subramaniam SR, Chesselet MF. Mitochondrial dysfunction and oxidative stress in Parkinson’s disease. Prog Neurobiol. 2013;106–107:17–32 (PubMed PMID: 23643800. Pubmed Central PMCID: 3742021).

    PubMed  Google Scholar 

  62. Kruse SE, Watt WC, Marcinek DJ, Kapur RP, Schenkman KA, Palmiter RD. Mice with mitochondrial complex I deficiency develop a fatal encephalomyopathy. Cell Metab. 2008;7(4):312–20 (PubMed PMID: 18396137. Pubmed Central PMCID: 2593686).

    PubMed Central  CAS  PubMed  Google Scholar 

  63. Varcin M, Bentea E, Michotte Y, Sarre S. Oxidative stress in genetic mouse models of Parkinson’s disease. Oxid Med Cell Longev. 2012;2012:624925 (PubMed PMID: 22829959. Pubmed Central PMCID: 3399377).

    PubMed Central  PubMed  Google Scholar 

  64. Lim KL, Zhang CW. Molecular events underlying Parkinson’s disease—an interwoven tapestry. Front Neurol. 2013;4:33 (PubMed PMID: 23580245. Pubmed Central PMCID: 3619247).

    PubMed Central  PubMed  Google Scholar 

  65. Stadtman ER, Levine RL. Free radical-mediated oxidation of free amino acids and amino acid residues in proteins. Amino Acids. 2003;25(3–4):207–18 (PubMed PMID: 14661084).

    CAS  PubMed  Google Scholar 

  66. Floriano-Sanchez E, Villanueva C, Medina-Campos ON, Rocha D, Sanchez-Gonzalez DJ, Cardenas-Rodriguez N, et al. Nordihydroguaiaretic acid is a potent in vitro scavenger of peroxynitrite, singlet oxygen, hydroxyl radical, superoxide anion and hypochlorous acid and prevents in vivo ozone-induced tyrosine nitration in lungs. Free Radic Res. 2006;40(5):523–33 (PubMed PMID: 16551579).

    CAS  PubMed  Google Scholar 

  67. Lotharius J, Brundin P. Pathogenesis of Parkinson’s disease: dopamine, vesicles and alpha-synuclein. Nat Rev Neurosci. 2002;3(12):932–42 (PubMed PMID: 12461550).

    CAS  PubMed  Google Scholar 

  68. Cohen G. Oxidative stress, mitochondrial respiration, and Parkinson’s disease. Ann N Y Acad Sci. 2000;899:112–20 (PubMed PMID: 10863533).

    CAS  PubMed  Google Scholar 

  69. Lawson LJ, Perry VH, Dri P, Gordon S. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience. 1990;39(1):151–70 (PubMed PMID: 2089275).

    CAS  PubMed  Google Scholar 

  70. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140(6):918–34 (PubMed PMID: 20303880. Pubmed Central PMCID: 2873093).

    PubMed Central  CAS  PubMed  Google Scholar 

  71. de Oliveira MR, da Rocha RF, Stertz L, Fries GR, de Oliveira DL, Kapczinski F, et al. Total and mitochondrial nitrosative stress, decreased brain-derived neurotrophic factor (BDNF) levels and glutamate uptake, and evidence of endoplasmic reticulum stress in the hippocampus of vitamin A-treated rats. Neurochem Res. 2011;36(3):506–17 (PubMed PMID: 21188516).

    PubMed  Google Scholar 

  72. Kumar C, Igbaria A, D’Autreaux B, Planson AG, Junot C, Godat E, et al. Glutathione revisited: a vital function in iron metabolism and ancillary role in thiol-redox control. EMBO J. 2011;30(10):2044–56 (PubMed PMID: 21478822. Pubmed Central PMCID: 3098478).

    PubMed Central  CAS  PubMed  Google Scholar 

  73. Martin HL, Teismann P. Glutathione—a review on its role and significance in Parkinson’s disease. FASEB J. 2009;23(10):3263–72 (PubMed PMID: 19542204).

    CAS  PubMed  Google Scholar 

  74. McCormack AL, Thiruchelvam M, Manning-Bog AB, Thiffault C, Langston JW, Cory-Slechta DA, et al. Environmental risk factors and Parkinson’s disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol Dis. 2002;10(2):119–27 (PubMed PMID: 12127150).

    CAS  PubMed  Google Scholar 

  75. Peng J, Stevenson FF, Doctrow SR, Andersen JK. Superoxide dismutase/catalase mimetics are neuroprotective against selective paraquat-mediated dopaminergic neuron death in the substantial nigra: implications for Parkinson disease. J Biol Chem. 2005;280(32):29194–8 (PubMed PMID: 15946937).

    CAS  PubMed  Google Scholar 

  76. Danielson SR, Andersen JK. Oxidative and nitrative protein modifications in Parkinson’s disease. Free Radic Biol Med. 2008;44(10):1787–94 (PubMed PMID: 18395015. Pubmed Central PMCID: 2422863).

    PubMed Central  CAS  PubMed  Google Scholar 

  77. Oueslati A, Fournier M, Lashuel HA. Role of post-translational modifications in modulating the structure, function and toxicity of alpha-synuclein: implications for Parkinson’s disease pathogenesis and therapies. Prog Brain Res. 2010;183:115–45 (PubMed PMID: 20696318).

    CAS  PubMed  Google Scholar 

  78. Xiang W, Schlachetzki JC, Helling S, Bussmann JC, Berlinghof M, Schaffer TE, et al. Oxidative stress-induced posttranslational modifications of alpha-synuclein: specific modification of alpha-synuclein by 4-hydroxy-2-nonenal increases dopaminergic toxicity. Mol Cell Neurosci. 2013;54:71–83 (PubMed PMID: 23369945).

    CAS  PubMed  Google Scholar 

  79. Winner B, Jappelli R, Maji SK, Desplats PA, Boyer L, Aigner S, et al. In vivo demonstration that alpha-synuclein oligomers are toxic. Proc Natl Acad Sci USA. 2011;108(10):4194–9 (PubMed PMID: 21325059. Pubmed Central PMCID: 3053976).

    PubMed Central  CAS  PubMed  Google Scholar 

  80. Bhat NR, Zhang P, Lee JC, Hogan EL. Extracellular signal-regulated kinase and p38 subgroups of mitogen-activated protein kinases regulate inducible nitric oxide synthase and tumor necrosis factor-alpha gene expression in endotoxin-stimulated primary glial cultures. J Neurosci. 1998;18(5):1633–41 (PubMed PMID: 9464988).

    CAS  PubMed  Google Scholar 

  81. Bianco F, Fumagalli M, Pravettoni E, D’Ambrosi N, Volonte C, Matteoli M, et al. Pathophysiological roles of extracellular nucleotides in glial cells: differential expression of purinergic receptors in resting and activated microglia. Brain ResBrain Res Rev. 2005;48(2):144–56 (PubMed PMID: 15850653).

    CAS  Google Scholar 

  82. Levesque S, Wilson B, Gregoria V, Thorpe LB, Dallas S, Polikov VS, et al. Reactive microgliosis: extracellular micro-calpain and microglia-mediated dopaminergic neurotoxicity. Brain. 2010;133(Pt 3):808–21 (PubMed PMID: 20123724. Pubmed Central PMCID: 2860703).

    PubMed Central  PubMed  Google Scholar 

  83. Verkhratsky A, Kettenmann H. Calcium signalling in glial cells. Trends Neurosci. 1996;19(8):346–52 (PubMed PMID: 8843604).

    CAS  PubMed  Google Scholar 

  84. Zhang W, Phillips K, Wielgus AR, Liu J, Albertini A, Zucca FA, et al. Neuromelanin activates microglia and induces degeneration of dopaminergic neurons: implications for progression of Parkinson’s disease. Neurotox Res. 2011;19(1):63–72 (PubMed PMID: 19957214. Pubmed Central PMCID: 3603276).

    PubMed Central  PubMed  Google Scholar 

  85. Hald A, Lotharius J. Oxidative stress and inflammation in Parkinson’s disease: is there a causal link? Exp Neurol. 2005;193(2):279–90 (PubMed PMID: 15869932).

    CAS  PubMed  Google Scholar 

  86. Hatcher JM, Pennell KD, Miller GW. Parkinson’s disease and pesticides: a toxicological perspective. Trends Pharmacol Sci. 2008;29(6):322–9 (PubMed PMID: 18453001).

    CAS  PubMed  Google Scholar 

  87. Li AA, Mink PJ, McIntosh LJ, Teta MJ, Finley B. Evaluation of epidemiologic and animal data associating pesticides with Parkinson’s disease. J Occup Environ Med. 2005;47(10):1059–87 (PubMed PMID: 16217247).

    PubMed  Google Scholar 

  88. Jackson-Lewis V, Blesa J, Przedborski S. Animal models of Parkinson’s disease. Parkinsonism Relat Disord. 2012;18(Suppl 1):S183–5 (PubMed PMID: 22166429).

    PubMed  Google Scholar 

  89. Greenamyre JT, Cannon JR, Drolet R, Mastroberardino PG. Lessons from the rotenone model of Parkinson’s disease. Trends Pharmacol Sci. 2010;31(4):141–2 (author reply 2–3. PubMed PMID: 20096940. Pubmed Central PMCID: 2846992).

    PubMed Central  CAS  PubMed  Google Scholar 

  90. Cabeza-Arvelaiz Y, Schiestl RH. Transcriptome analysis of a rotenone model of parkinsonism reveals complex I-tied and -untied toxicity mechanisms common to neurodegenerative diseases. PLoS One. 2012;7(9):e44700 (PubMed PMID: 22970289. Pubmed Central PMCID: 3436760).

    PubMed Central  CAS  PubMed  Google Scholar 

  91. Gyulkhandanyan AV, Feeney CJ, Pennefather PS. Modulation of mitochondrial membrane potential and reactive oxygen species production by copper in astrocytes. J Neurochem. 2003;87(2):448–60 (PubMed PMID: 14511122).

    CAS  PubMed  Google Scholar 

  92. Arnold B, Cassady SJ, VanLaar VS, Berman SB. Integrating multiple aspects of mitochondrial dynamics in neurons: age-related differences and dynamic changes in a chronic rotenone model. Neurobiol Dis. 2011;41(1):189–200 (PubMed PMID: 20850532. Pubmed Central PMCID: 3021420).

    PubMed Central  CAS  PubMed  Google Scholar 

  93. Choi WS, Palmiter RD, Xia Z. Loss of mitochondrial complex I activity potentiates dopamine neuron death induced by microtubule dysfunction in a Parkinson’s disease model. J Cell Biol. 2011;192(5):873–82 (PubMed PMID: 21383081. Pubmed Central PMCID: 3051820).

    PubMed Central  CAS  PubMed  Google Scholar 

  94. Sanders LH, Greenamyre JT. Oxidative damage to macromolecules in human Parkinson disease and the rotenone model. Free Radic Biol Med. 2013;62:111–20 (PubMed PMID: 23328732. Pubmed Central PMCID: 3677955).

    PubMed Central  CAS  PubMed  Google Scholar 

  95. Sherer TB, Betarbet R, Testa CM, Seo BB, Richardson JR, Kim JH, et al. Mechanism of toxicity in rotenone models of Parkinson’s disease. J Neurosci. 2003;23(34):10756–64 (PubMed PMID: 14645467).

    CAS  PubMed  Google Scholar 

  96. Marella M, Seo BB, Nakamaru-Ogiso E, Greenamyre JT, Matsuno-Yagi A, Yagi T. Protection by the NDI1 gene against neurodegeneration in a rotenone rat model of Parkinson’s disease. PLoS One. 2008;3(1):e1433 (PubMed PMID: 18197244. Pubmed Central PMCID: 2175531).

    PubMed Central  PubMed  Google Scholar 

  97. Sterky FH, Hoffman AF, Milenkovic D, Bao B, Paganelli A, Edgar D, et al. Altered dopamine metabolism and increased vulnerability to MPTP in mice with partial deficiency of mitochondrial complex I in dopamine neurons. Hum Mol Genet. 2012;21(5):1078–89 (PubMed PMID: 22090423. Pubmed Central PMCID: 3277308).

    PubMed Central  CAS  PubMed  Google Scholar 

  98. Gao HM, Liu B, Hong JS. Critical role for microglial NADPH oxidase in rotenone-induced degeneration of dopaminergic neurons. J Neurosci. 2003;23(15):6181–7 (PubMed PMID: 12867501).

    CAS  PubMed  Google Scholar 

  99. Tanner CM, Kamel F, Ross GW, Hoppin JA, Goldman SM, Korell M, et al. Rotenone, paraquat, and Parkinson’s disease. Environ Health Perspect. 2011;119(6):866–72 (PubMed PMID: 21269927. Pubmed Central PMCID: 3114824).

    PubMed Central  CAS  PubMed  Google Scholar 

  100. Wang A, Costello S, Cockburn M, Zhang X, Bronstein J, Ritz B. Parkinson’s disease risk from ambient exposure to pesticides. Eur J Epidemiol. 2011;26(7):547–55 (PubMed PMID: 21505849. Pubmed Central PMCID: 3643971).

    PubMed Central  CAS  PubMed  Google Scholar 

  101. Cocheme HM, Murphy MP. Complex I is the major site of mitochondrial superoxide production by paraquat. J Biol Chem. 2008;283(4):1786–98 (PubMed PMID: 18039652).

    CAS  PubMed  Google Scholar 

  102. Richardson JR, Quan Y, Sherer TB, Greenamyre JT, Miller GW. Paraquat neurotoxicity is distinct from that of MPTP and rotenone. Toxicol Sci. 2005;88(1):193–201 (PubMed PMID: 16141438).

    CAS  PubMed  Google Scholar 

  103. Prasad K, Winnik B, Thiruchelvam MJ, Buckley B, Mirochnitchenko O, Richfield EK. Prolonged toxicokinetics and toxicodynamics of paraquat in mouse brain. Environ Health Perspect. 2007;115(10):1448–53 (PubMed PMID: 17938734. Pubmed Central PMCID: 2022643).

    PubMed Central  CAS  PubMed  Google Scholar 

  104. Brooks AI, Chadwick CA, Gelbard HA, Cory-Slechta DA, Federoff HJ. Paraquat elicited neurobehavioral syndrome caused by dopaminergic neuron loss. Brain Res. 1999;823(1–2):1–10 (PubMed PMID: 10095006).

    CAS  PubMed  Google Scholar 

  105. McCormack AL, Di Monte DA. Effects of L-dopa and other amino acids against paraquat-induced nigrostriatal degeneration. J Neurochem. 2003;85(1):82–6 (PubMed PMID: 12641729).

    CAS  PubMed  Google Scholar 

  106. Ramachandiran S, Hansen JM, Jones DP, Richardson JR, Miller GW. Divergent mechanisms of paraquat, MPP+, and rotenone toxicity: oxidation of thioredoxin and caspase-3 activation. Toxicol Sci. 2007;95(1):163–71 (PubMed PMID: 17018646).

    CAS  PubMed  Google Scholar 

  107. Castello PR, Drechsel DA, Patel M. Mitochondria are a major source of paraquat-induced reactive oxygen species production in the brain. J Biol Chem. 2007;282(19):14186–93 (PubMed PMID: 17389593. Pubmed Central PMCID: 3088512).

    PubMed Central  CAS  PubMed  Google Scholar 

  108. Jones GM, Vale JA. Mechanisms of toxicity, clinical features, and management of diquat poisoning: a review. J Toxicol Clin Toxicol. 2000;38(2):123–8 (PubMed PMID: 10778908).

    CAS  PubMed  Google Scholar 

  109. Yumino K, Kawakami I, Tamura M, Hayashi T, Nakamura M. Paraquat- and diquat-induced oxygen radical generation and lipid peroxidation in rat brain microsomes. J Biochem. 2002;131(4):565–70 (PubMed PMID: 11926994).

    CAS  PubMed  Google Scholar 

  110. Miller RL, Sun GY, Sun AY. Cytotoxicity of paraquat in microglial cells: involvement of PKCdelta- and ERK1/2-dependent NADPH oxidase. Brain Res. 2007;1167:129–39 (PubMed PMID: 17662968. Pubmed Central PMCID: 2084263).

    PubMed Central  CAS  PubMed  Google Scholar 

  111. Purisai MG, McCormack AL, Cumine S, Li J, Isla MZ, Di Monte DA. Microglial activation as a priming event leading to paraquat-induced dopaminergic cell degeneration. Neurobiol Dis. 2007;25(2):392–400 (PubMed PMID: 17166727. Pubmed Central PMCID: 2001246).

    PubMed Central  CAS  PubMed  Google Scholar 

  112. Bonneh-Barkay D, Reaney SH, Langston WJ, Di Monte DA. Redox cycling of the herbicide paraquat in microglial cultures. Brain Res Mol Brain Res. 2005;134(1):52–6 (PubMed PMID: 15790529).

    CAS  PubMed  Google Scholar 

  113. Fussell KC, Udasin RG, Gray JP, Mishin V, Smith PJ, Heck DE, et al. Redox cycling and increased oxygen utilization contribute to diquat-induced oxidative stress and cytotoxicity in Chinese hamster ovary cells overexpressing NADPH-cytochrome P450 reductase. Free Radic Biol Med. 2011;50(7):874–82 (PubMed PMID: 21215309. Pubmed Central PMCID: 3647689).

    PubMed Central  CAS  PubMed  Google Scholar 

  114. Van Remmen H, Qi W, Sabia M, Freeman G, Estlack L, Yang H, et al. Multiple deficiencies in antioxidant enzymes in mice result in a compound increase in sensitivity to oxidative stress. Free Radic Biol Med. 2004;36(12):1625–34 (PubMed PMID: 15182862).

    PubMed  Google Scholar 

  115. Mockett RJ, Bayne AC, Kwong LK, Orr WC, Sohal RS. Ectopic expression of catalase in Drosophila mitochondria increases stress resistance but not longevity. Free Radic Biol Med. 2003;34(2):207–17 (PubMed PMID: 12521602).

    CAS  PubMed  Google Scholar 

  116. Tien Nguyen-nhu N, Knoops B. Mitochondrial and cytosolic expression of human peroxiredoxin 5 in Saccharomyces cerevisiae protect yeast cells from oxidative stress induced by paraquat. FEBS Lett. 2003;544(1–3):148–52 (PubMed PMID: 12782306).

    PubMed  Google Scholar 

  117. Cantu D, Fulton RE, Drechsel DA, Patel M. Mitochondrial aconitase knockdown attenuates paraquat-induced dopaminergic cell death via decreased cellular metabolism and release of iron and H(2)O(2). J Neurochem. 2011;118(1):79–92 (PubMed PMID: 21517855. Pubmed Central PMCID: 3182850).

    PubMed Central  CAS  PubMed  Google Scholar 

  118. Gonzalez-Polo RA, Rodriguez-Martin A, Moran JM, Niso M, Soler G, Fuentes JM. Paraquat-induced apoptotic cell death in cerebellar granule cells. Brain Res. 2004;1011(2):170–6 (PubMed PMID: 15157803).

    CAS  PubMed  Google Scholar 

  119. Minelli A, Conte C, Grottelli S, Bellezza I, Emiliani C, Bolanos JP. Cyclo(His-Pro) up-regulates heme oxygenase 1 via activation of Nrf2-ARE signalling. J Neurochem. 2009;111(4):956–66 (PubMed PMID: 19735445).

    CAS  PubMed  Google Scholar 

  120. Kanthasamy AG, Kitazawa M, Kanthasamy A, Anantharam V. Dieldrin-induced neurotoxicity: relevance to Parkinson’s disease pathogenesis. Neurotoxicology. 2005;26(4):701–19 (PubMed PMID: 16112328).

    CAS  PubMed  Google Scholar 

  121. Corrigan FM, French M, Murray L. Organochlorine compounds in human brain. Hum Exp Toxicol. 1996;15(3):262–4 (PubMed PMID: 8839217).

    CAS  PubMed  Google Scholar 

  122. Corrigan FM, Murray L, Wyatt CL, Shore RF. Diorthosubstituted polychlorinated biphenyls in caudate nucleus in Parkinson’s disease. Exp Neurol. 1998;150(2):339–42 (PubMed PMID: 9527905).

    CAS  PubMed  Google Scholar 

  123. Corrigan FM, Wienburg CL, Shore RF, Daniel SE, Mann D. Organochlorine insecticides in substantia nigra in Parkinson’s disease. J Toxicol Environ Health A. 2000;59(4):229–34 (PubMed PMID: 10706031).

    CAS  PubMed  Google Scholar 

  124. Fleming L, Mann JB, Bean J, Briggle T, Sanchez-Ramos JR. Parkinson’s disease and brain levels of organochlorine pesticides. Ann Neurol. 1994;36(1):100–3 (PubMed PMID: 7517654).

    CAS  PubMed  Google Scholar 

  125. Bachowski S, Kolaja KL, Xu Y, Ketcham CA, Stevenson DE, Walborg EF, Jr., et al. Role of oxidative stress in the mechanism of dieldrin’s hepatotoxicity. Ann Clin Lab Sci. 1997;27(3):196–209 (PubMed PMID: 9142372).

    CAS  PubMed  Google Scholar 

  126. Chun HS, Gibson GE, DeGiorgio LA, Zhang H, Kidd VJ, Son JH. Dopaminergic cell death induced by MPP(+), oxidant and specific neurotoxicants shares the common molecular mechanism. J Neurochem. 2001;76(4):1010–21 (PubMed PMID: 11181820).

    CAS  PubMed  Google Scholar 

  127. Kannan K, Holcombe RF, Jain SK, Alvarez-Hernandez X, Chervenak R, Wolf RE, et al. Evidence for the induction of apoptosis by endosulfan in a human T-cell leukemic line. Mol Cell Biochem. 2000;205(1–2):53–66 (PubMed PMID: 10821422).

    CAS  PubMed  Google Scholar 

  128. Kitazawa M, Anantharam V, Kanthasamy AG. Dieldrin-induced oxidative stress and neurochemical changes contribute to apoptopic cell death in dopaminergic cells. Free Radic Biol Med. 2001;31(11):1473–85 (PubMed PMID: 11728820).

    CAS  PubMed  Google Scholar 

  129. Kanthasamy AG, Kitazawa M, Yang Y, Anantharam V, Kanthasamy A. Environmental neurotoxin dieldrin induces apoptosis via caspase-3-dependent proteolytic activation of protein kinase C delta (PKCdelta): implications for neurodegeneration in Parkinson’s disease. Mol Brain. 2008;1:12 (PubMed PMID: 18945348. Pubmed Central PMCID: 2584097).

    PubMed Central  PubMed  Google Scholar 

  130. Saminathan H, Asaithambi A, Anantharam V, Kanthasamy AG, Kanthasamy A. Environmental neurotoxic pesticide dieldrin activates a non receptor tyrosine kinase to promote PKCdelta-mediated dopaminergic apoptosis in a dopaminergic neuronal cell model. Neurotoxicology. 2011;32(5):567–77 (PubMed PMID: 21801747. Pubmed Central PMCID: 3328137).

    PubMed Central  CAS  PubMed  Google Scholar 

  131. Miller GW, Kirby ML, Levey AI, Bloomquist JR. Heptachlor alters expression and function of dopamine transporters. Neurotoxicology. 1999;20(4):631–7 (PubMed PMID: 10499361).

    CAS  PubMed  Google Scholar 

  132. Miller GW, Erickson JD, Perez JT, Penland SN, Mash DC, Rye DB, et al. Immunochemical analysis of vesicular monoamine transporter (VMAT2) protein in Parkinson’s disease. Exp Neurol. 1999;156(1):138–48 (PubMed PMID: 10192785).

    CAS  PubMed  Google Scholar 

  133. Hatcher JM, Richardson JR, Guillot TS, McCormack AL, Di Monte DA, Jones DP, et al. Dieldrin exposure induces oxidative damage in the mouse nigrostriatal dopamine system. Exp Neurol. 2007;204(2):619–30 (PubMed PMID: 17291500. Pubmed Central PMCID: 1896133).

    PubMed Central  CAS  PubMed  Google Scholar 

  134. Ebrahimi-Fakhari D, Cantuti-Castelvetri I, Fan Z, Rockenstein E, Masliah E, Hyman BT, et al. Distinct roles in vivo for the ubiquitin-proteasome system and the autophagy-lysosomal pathway in the degradation of alpha-synuclein. J Neurosci. 2011;31(41):14508–20 (PubMed PMID: 21994367. Pubmed Central PMCID: 3587176).

    PubMed Central  CAS  PubMed  Google Scholar 

  135. Nedelsky NB, Todd PK, Taylor JP. Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection. Biochim Biophys Acta. 2008;1782(12):691–9 (PubMed PMID: 18930136. Pubmed Central PMCID: 2621359).

    PubMed Central  CAS  PubMed  Google Scholar 

  136. Korolchuk VI, Menzies FM, Rubinsztein DC. Mechanisms of cross-talk between the ubiquitin-proteasome and autophagy-lysosome systems. FEBS Lett. 2010;584(7):1393–8 (PubMed PMID: 20040365).

    CAS  PubMed  Google Scholar 

  137. Lilienbaum A. Relationship between the proteasomal system and autophagy. Int J Biochem Mol Biol. 2013;4(1):1–26 (PubMed PMID: 23638318. Pubmed Central PMCID: 3627065).

    PubMed Central  CAS  PubMed  Google Scholar 

  138. Korolchuk VI, Menzies FM, Rubinsztein DC. A novel link between autophagy and the ubiquitin-proteasome system. Autophagy. 2009;5(6):862–3 (PubMed PMID: 19458478).

    PubMed  Google Scholar 

  139. van Wijk SJ Timmers HT. The family of ubiquitin-conjugating enzymes (E2s): deciding between life and death of proteins. FASEB J. 2010;24(4):981–93 (PubMed PMID: 19940261).

    PubMed  Google Scholar 

  140. Pickart CM. Mechanisms underlying ubiquitination. Annu Rev Biochem. 2001;70:503–33 (PubMed PMID: 11395416).

    CAS  PubMed  Google Scholar 

  141. Nandi D, Tahiliani P, Kumar A, Chandu D. The ubiquitin-proteasome system. J Biosci. 2006;31(1):137–55 (PubMed PMID: 16595883).

    CAS  PubMed  Google Scholar 

  142. Tanaka K. The proteasome: overview of structure and functions. Proc Jpn Acad Ser B Phys Biol Sci. 2009;85(1):12–36 (PubMed PMID: 19145068. Pubmed Central PMCID: 3524306).

    PubMed Central  CAS  PubMed  Google Scholar 

  143. Cook C, Petrucelli L. A critical evaluation of the ubiquitin-proteasome system in Parkinson’s disease. Biochim Biophys Acta. 2009;1792(7):664–75 (PubMed PMID: 19419700. Pubmed Central PMCID: 2828612).

    PubMed Central  CAS  PubMed  Google Scholar 

  144. Rinetti GV, Schweizer FE. Ubiquitination acutely regulates presynaptic neurotransmitter release in mammalian neurons. J Neurosci. 2010;30(9):3157–66 (PubMed PMID: 20203175. Pubmed Central PMCID: 2905680).

    PubMed Central  CAS  PubMed  Google Scholar 

  145. d’Azzo A, Bongiovanni A, Nastasi T. E3 ubiquitin ligases as regulators of membrane protein trafficking and degradation. Traffic. 2005;6(6):429–41 (PubMed PMID: 15882441).

    PubMed  Google Scholar 

  146. Ulrich HD, Walden H. Ubiquitin signalling in DNA replication and repair. Nat Rev Mol Cell Biol. 2010;11(7):479–89 (PubMed PMID: 20551964).

    CAS  PubMed  Google Scholar 

  147. McNaught KS, Jackson T, JnoBaptiste R, Kapustin A, Olanow CW. Proteasomal dysfunction in sporadic Parkinson’s disease. Neurology. 2006;66(10 Suppl 4):S37–49 (PubMed PMID: 16717251).

    CAS  PubMed  Google Scholar 

  148. Moore DJ, West AB, Dawson VL, Dawson TM. Molecular pathophysiology of Parkinson’s disease. Annu Rev Neurosci. 2005;28:57–87 (PubMed PMID: 16022590).

    CAS  PubMed  Google Scholar 

  149. Ying Z, Wang H, Wang G. The ubiquitin proteasome system as a potential target for the treatment of neurodegenerative diseases. Curr Pharm Des. 2013;19(18):3305–14 (PubMed PMID: 23151138).

    CAS  PubMed  Google Scholar 

  150. Imai Y, Soda M, Hatakeyama S, Akagi T, Hashikawa T, Nakayama KI, et al. CHIP is associated with Parkin, a gene responsible for familial Parkinson’s disease, and enhances its ubiquitin ligase activity. Mol Cell. 2002;10(1):55–67 (PubMed PMID: 12150907).

    CAS  PubMed  Google Scholar 

  151. Fishman-Jacob T, Reznichenko L, Youdim MB, Mandel SA. A sporadic Parkinson disease model via silencing of the ubiquitin-proteasome/E3 ligase component SKP1A. J Biol Chem. 2009;284(47):32835–45 (PubMed PMID: 19748892. Pubmed Central PMCID: 2781700).

    PubMed Central  CAS  PubMed  Google Scholar 

  152. McNaught KS, Olanow CW, Halliwell B, Isacson O, Jenner P. Failure of the ubiquitin-proteasome system in Parkinson’s disease. Nat Rev Neurosci. 2001;2(8):589–94 (PubMed PMID: 11484002).

    CAS  PubMed  Google Scholar 

  153. Haigis MC, Yankner BA. The aging stress response. Mol Cell. 2010;40(2):333–44 (PubMed PMID: 20965426. Pubmed Central PMCID: 2987618).

    PubMed Central  CAS  PubMed  Google Scholar 

  154. Surguchov A. Molecular and cellular biology of synucleins. Int Rev Cell Mol Biol. 2008;270:225–317 (PubMed PMID: 19081538).

    CAS  PubMed  Google Scholar 

  155. Surguchov A. Synucleins: are they two-edged swords? J Neurosci Res. 2013;91(2):161–6 (PubMed PMID: 23150342).

    CAS  PubMed  Google Scholar 

  156. Cookson MR. alpha-Synuclein and neuronal cell death. Mol Neurodegener. 2009;4:9 (PubMed PMID: 19193223. Pubmed Central PMCID: 2646729).

    PubMed Central  PubMed  Google Scholar 

  157. Takalo M, Salminen A, Soininen H, Hiltunen M, Haapasalo A. Protein aggregation and degradation mechanisms in neurodegenerative diseases. Am J Neurodegener Dis. 2013;2(1):1–14 (PubMed PMID: 23516262. Pubmed Central PMCID: 3601466).

    PubMed Central  PubMed  Google Scholar 

  158. Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, et al. Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J. 2005;19(6):533–42 (PubMed PMID: 15791003).

    CAS  PubMed  Google Scholar 

  159. Rhodes SL, Fitzmaurice AG, Cockburn M, Bronstein JM, Sinsheimer JS, Ritz B. Pesticides that inhibit the ubiquitin-proteasome system: effect measure modification by genetic variation in SKP1 in Parkinsons disease. Environ Res. 2013;126:1–8 (PubMed PMID: 23988235. Pubmed Central PMCID: 3832349).

    CAS  PubMed  Google Scholar 

  160. Liao EH, Hung W, Abrams B, Zhen M. An SCF-like ubiquitin ligase complex that controls presynaptic differentiation. Nature. 2004;430(6997):345–50 (PubMed PMID: 15208641).

    CAS  PubMed  Google Scholar 

  161. Cannon JR, Tapias V, Na HM, Honick AS, Drolet RE, Greenamyre JT. A highly reproducible rotenone model of Parkinson’s disease. Neurobiol Dis. 2009;34(2):279–90 (PubMed PMID: 19385059. Pubmed Central PMCID: 2757935).

    PubMed Central  CAS  PubMed  Google Scholar 

  162. Fornai F, Schluter OM, Lenzi P, Gesi M, Ruffoli R, Ferrucci M, et al. Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and alpha-synuclein. Proc Natl Acad Sci USA. 2005;102(9):3413–8 (PubMed PMID: 15716361. Pubmed Central PMCID: 552938).

    PubMed Central  CAS  PubMed  Google Scholar 

  163. Pan-Montojo FJ, Funk RH. Oral administration of rotenone using a gavage and image analysis of alpha-synuclein inclusions in the enteric nervous system. J Vis Exp. 2010 (44). PubMed PMID: 21085094. Pubmed Central PMCID: 3280635.

    Google Scholar 

  164. Drolet RE, Cannon JR, Montero L, Greenamyre JT. Chronic rotenone exposure reproduces Parkinson’s disease gastrointestinal neuropathology. Neurobiol Dis. 2009;36(1):96–102 (PubMed PMID: 19595768).

    CAS  PubMed  Google Scholar 

  165. Krishnan S, Chi EY, Wood SJ, Kendrick BS, Li C, Garzon-Rodriguez W, et al. Oxidative dimer formation is the critical rate-limiting step for Parkinson’s disease alpha-synuclein fibrillogenesis. Biochemistry. 2003;42(3):829–37 (PubMed PMID: 12534296).

    CAS  PubMed  Google Scholar 

  166. Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA. The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J Biol Chem. 2002;277(3):1641–4 (PubMed PMID: 11707429).

    CAS  PubMed  Google Scholar 

  167. Valente EM, Arena G, Torosantucci L, Gelmetti V. Molecular pathways in sporadic PD. Parkinsonism Relat Disord. 2012;18(Suppl 1):S71–3 (PubMed PMID: 22166460).

    PubMed  Google Scholar 

  168. Uversky VN, Li J, Fink AL. Pesticides directly accelerate the rate of alpha-synuclein fibril formation: a possible factor in Parkinson’s disease. FEBS Lett. 2001;500(3):105–8 (PubMed PMID: 11445065).

    CAS  PubMed  Google Scholar 

  169. Fernagut PO, Hutson CB, Fleming SM, Tetreaut NA, Salcedo J, Masliah E, et al. Behavioral and histopathological consequences of paraquat intoxication in mice: effects of alpha-synuclein over-expression. Synapse. 2007;61(12):991–1001 (PubMed PMID: 17879265. Pubmed Central PMCID: 3097512).

    PubMed Central  CAS  PubMed  Google Scholar 

  170. Nuber S, Petrasch-Parwez E, Winner B, Winkler J, von Horsten S, Schmidt T, et al. Neurodegeneration and motor dysfunction in a conditional model of Parkinson’s disease. J Neurosci. 2008;28(10):2471–84 (PubMed PMID: 18322092).

    CAS  PubMed  Google Scholar 

  171. Cristovao AC, Guhathakurta S, Bok E, Je G, Yoo SD, Choi DH, et al. NADPH oxidase 1 mediates alpha-synucleinopathy in Parkinson’s disease. J Neurosci. 2012;32(42):14465–77 (PubMed PMID: 23077033. Pubmed Central PMCID: 3501265).

    PubMed Central  CAS  PubMed  Google Scholar 

  172. Thiruchelvam M, Richfield EK, Baggs RB, Tank AW, Cory-Slechta DA. The nigrostriatal dopaminergic system as a preferential target of repeated exposures to combined paraquat and maneb: implications for Parkinson’s disease. J Neurosci. 2000;20(24):9207–14 (PubMed PMID: 11124998).

    CAS  PubMed  Google Scholar 

  173. Thiruchelvam MJ, Powers JM, Cory-Slechta DA, Richfield EK. Risk factors for dopaminergic neuron loss in human alpha-synuclein transgenic mice. Eur J Neurosci. 2004;19(4):845–54 (PubMed PMID: 15009131).

    CAS  PubMed  Google Scholar 

  174. Norris EH, Uryu K, Leight S, Giasson BI, Trojanowski JQ, Lee VM. Pesticide exposure exacerbates alpha-synucleinopathy in an A53T transgenic mouse model. Am J Pathol. 2007;170(2):658–66 (PubMed PMID: 17255333. Pubmed Central PMCID: 1851868).

    PubMed Central  CAS  PubMed  Google Scholar 

  175. Branco DM, Arduino DM, Esteves AR, Silva DF, Cardoso SM, Oliveira CR. Cross-talk between mitochondria and proteasome in Parkinson’s disease pathogenesis. Front Aging Neurosci. 2010;2:17 (PubMed PMID: 20577640. Pubmed Central PMCID: 2890153).

    PubMed Central  CAS  PubMed  Google Scholar 

  176. Yang W, Tiffany-Castiglioni E. The bipyridyl herbicide paraquat induces proteasome dysfunction in human neuroblastoma SH-SY5Y cells. J Toxicol Environ Health A. 2007;70(21):1849–57 (PubMed PMID: 17934957).

    CAS  PubMed  Google Scholar 

  177. Wills J, Credle J, Oaks AW, Duka V, Lee JH, Jones J, et al. Paraquat, but not maneb, induces synucleinopathy and tauopathy in striata of mice through inhibition of proteasomal and autophagic pathways. PloS one. 2012;7(1):e30745 (PubMed PMID: 22292029. Pubmed Central PMCID: 3264632).

    PubMed Central  CAS  PubMed  Google Scholar 

  178. Perfeito R, Cunha-Oliveira T, Rego AC. Reprint of: revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease-resemblance to the effect of amphetamine drugs of abuse. Free Radic Biol Med. 2013;62:186–201 (PubMed PMID: 23743292).

    CAS  PubMed  Google Scholar 

  179. Sun F, Anantharam V, Latchoumycandane C, Kanthasamy A, Kanthasamy AG. Dieldrin induces ubiquitin-proteasome dysfunction in alpha-synuclein overexpressing dopaminergic neuronal cells and enhances susceptibility to apoptotic cell death. J Pharmacol Exp Ther. 2005;315(1):69–79 (PubMed PMID: 15987830).

    CAS  PubMed  Google Scholar 

  180. Son JH, Shim JH, Kim KH, Ha JY, Han JY. Neuronal autophagy and neurodegenerative diseases. Exp Mol Med. 2012;44(2):89–98 (PubMed PMID: 22257884. Pubmed Central PMCID: 3296817).

    PubMed Central  CAS  PubMed  Google Scholar 

  181. Banerjee R, Beal MF, Thomas B. Autophagy in neurodegenerative disorders: pathogenic roles and therapeutic implications. Trends Neurosci. 2010;33(12):541–9 (PubMed PMID: 20947179. Pubmed Central PMCID: 2981680).

    PubMed Central  CAS  PubMed  Google Scholar 

  182. Ross CA, Poirier MA. Protein aggregation and neurodegenerative disease. Nat Med. 2004;10(Suppl):S10–7 (PubMed PMID: 15272267).

    PubMed  Google Scholar 

  183. Taylor JP, Hardy J, Fischbeck KH. Toxic proteins in neurodegenerative disease. Science. 2002;296(5575):1991–5 (PubMed PMID: 12065827).

    CAS  PubMed  Google Scholar 

  184. Boland B, Nixon RA. Neuronal macroautophagy: from development to degeneration. Mol Aspects Med. 2006;27(5–6):503–19 (PubMed PMID: 16999991).

    CAS  PubMed  Google Scholar 

  185. Rideout HJ, Lang-Rollin I, Stefanis L. Involvement of macroautophagy in the dissolution of neuronal inclusions. Int J Biochem Cell Biol. 2004;36(12):2551–62 (PubMed PMID: 15325592).

    CAS  PubMed  Google Scholar 

  186. Rubinsztein DC, Gestwicki JE, Murphy LO, Klionsky DJ. Potential therapeutic applications of autophagy. Nat Rev Drug Discov. 2007;6(4):304–12 (PubMed PMID: 17396135).

    CAS  PubMed  Google Scholar 

  187. Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell. 2004;6(4):463–77 (PubMed PMID: 15068787).

    CAS  PubMed  Google Scholar 

  188. Ohsumi Y. Molecular dissection of autophagy: two ubiquitin-like systems. Nat Rev Mol Cell Biol. 2001;2(3):211–6 (PubMed PMID: 11265251).

    CAS  PubMed  Google Scholar 

  189. Mizushima N, Sugita H, Yoshimori T, Ohsumi Y. A new protein conjugation system in human. The counterpart of the yeast Apg12p conjugation system essential for autophagy. J Biol Chem. 1998;273(51):33889–92 (PubMed PMID: 9852036).

    CAS  PubMed  Google Scholar 

  190. Mizushima N, Yamamoto A, Hatano M, Kobayashi Y, Kabeya Y, Suzuki K, et al. Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol. 2001;152(4):657–68 (PubMed PMID: 11266458. Pubmed Central PMCID: 2195787).

    PubMed Central  CAS  PubMed  Google Scholar 

  191. Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med. 2013;19(8):983–97 (PubMed PMID: 23921753).

    CAS  PubMed  Google Scholar 

  192. Li WW, Li J, Bao JK. Microautophagy: lesser-known self-eating. Cell Mol Life Sci. 2012;69(7):1125–36 (PubMed PMID: 22080117).

    CAS  PubMed  Google Scholar 

  193. Bejarano E, Cuervo AM. Chaperone-mediated autophagy. Proc Am Thorac Soc. 2010;7(1):29–39 (PubMed PMID: 20160146. Pubmed Central PMCID: 3137147).

    PubMed Central  PubMed  Google Scholar 

  194. Xiong N, Zhang Z, Huang J, Chen C, Zhang Z, Jia M, et al. VEGF-expressing human umbilical cord mesenchymal stem cells, an improved therapy strategy for Parkinson’s disease. Gene Ther. 2011;18(4):394–402 (PubMed PMID: 21107440).

    CAS  PubMed  Google Scholar 

  195. Xiong N, Cao X, Zhang Z, Huang J, Chen C, Zhang Z, et al. Long-term efficacy and safety of human umbilical cord mesenchymal stromal cells in rotenone-induced hemiparkinsonian rats. Biol Blood Marrow Transplant. 2010;16(11):1519–29 (PubMed PMID: 20542126).

    PubMed  Google Scholar 

  196. Pan-Montojo F, Anichtchik O, Dening Y, Knels L, Pursche S, Jung R, et al. Progression of Parkinson’s disease pathology is reproduced by intragastric administration of rotenone in mice. PLoS One. 2010;5(1):e8762 (PubMed PMID: 20098733. Pubmed Central PMCID: 2808242).

    PubMed Central  PubMed  Google Scholar 

  197. Xiong N, Xiong J, Jia M, Liu L, Zhang X, Chen Z, et al. The role of autophagy in Parkinson’s disease: rotenone-based modeling. Behav Brain Funct. 2013;9:13 (PubMed PMID: 23497442. Pubmed Central PMCID: 3606411).

    PubMed Central  CAS  PubMed  Google Scholar 

  198. Mili A, Ben Charfeddine I, Mamai O, Abdelhak S, Adala L, Amara A, et al. Molecular and biochemical characterization of Tunisian patients with glycogen storage disease type III. J Hum Genet. 2012;57(3):170–5 (PubMed PMID: 22089644).

    CAS  PubMed  Google Scholar 

  199. Pan T, Rawal P, Wu Y, Xie W, Jankovic J, Le W. Rapamycin protects against rotenone-induced apoptosis through autophagy induction. Neuroscience. 2009;164(2):541–51 (PubMed PMID: 19682553).

    CAS  PubMed  Google Scholar 

  200. Filomeni G, Graziani I, De Zio D, Dini L, Centonze D, Rotilio G, et al. Neuroprotection of kaempferol by autophagy in models of rotenone-mediated acute toxicity: possible implications for Parkinson’s disease. Neurobiol Aging. 2012;33(4):767–85 (PubMed PMID: 20594614).

    CAS  PubMed  Google Scholar 

  201. Dadakhujaev S, Noh HS, Jung EJ, Cha JY, Baek SM, Ha JH, et al. Autophagy protects the rotenone-induced cell death in alpha-synuclein overexpressing SH-SY5Y cells. Neurosci Lett. 2010;472(1):47–52 (PubMed PMID: 20117172).

    CAS  PubMed  Google Scholar 

  202. Giordano S, Dodson M, Ravi S, Redmann M, Ouyang X, Darley Usmar VM, et al. Bioenergetic adaptation in response to autophagy regulators during rotenone exposure. J Neurochem. 2014;131:625–33 (PubMed PMID: 25081478).

    CAS  PubMed  Google Scholar 

  203. Chu CT, Ji J, Dagda RK, Jiang JF, Tyurina YY, Kapralov AA, et al. Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells. Nat Cell Biol. 2013;15(10):1197–205 (PubMed PMID: 24036476. Pubmed Central PMCID: 3806088).

    PubMed Central  CAS  PubMed  Google Scholar 

  204. Gonzalez-Polo RA, Niso-Santano M, Ortiz-Ortiz MA, Gomez-Martin A, Moran JM, Garcia-Rubio L, et al. Relationship between autophagy and apoptotic cell death in human neuroblastoma cells treated with paraquat: could autophagy be a “brake” in paraquat-induced apoptotic death? Autophagy. 2007;3(4):366–7 (PubMed PMID: 17438367).

    CAS  PubMed  Google Scholar 

  205. Gonzalez-Polo RA, Niso-Santano M, Ortiz-Ortiz MA, Gomez-Martin A, Moran JM, Garcia-Rubio L, et al. Inhibition of paraquat-induced autophagy accelerates the apoptotic cell death in neuroblastoma SH-SY5Y cells. Toxicol Sci. 2007;97(2):448–58 (PubMed PMID: 17341480).

    CAS  PubMed  Google Scholar 

  206. Garcia-Garcia A, Anandhan A, Burns M, Chen H, Zhou Y, Franco R. Impairment of Atg5-dependent autophagic flux promotes paraquat- and MPP(+)-induced apoptosis but not rotenone or 6-hydroxydopamine toxicity. Toxicol Sci. 2013;136(1):166–82 (PubMed PMID: 23997112. Pubmed Central PMCID: 3829573).

    PubMed Central  CAS  PubMed  Google Scholar 

  207. Chen YW, Yang YT, Hung DZ, Su CC, Chen KL. Paraquat induces lung alveolar epithelial cell apoptosis via Nrf-2-regulated mitochondrial dysfunction and ER stress. Arch Toxicol. 2012;86(10):1547–58 (PubMed PMID: 22678742).

    CAS  PubMed  Google Scholar 

  208. Omura T, Asari M, Yamamoto J, Oka K, Hoshina C, Maseda C, et al. Sodium tauroursodeoxycholate prevents paraquat-induced cell death by suppressing endoplasmic reticulum stress responses in human lung epithelial A549 cells. Biochem Biophys Res Commun. 2013;432(4):689–94 (PubMed PMID: 23416354).

    CAS  PubMed  Google Scholar 

  209. Yang W, Tiffany-Castiglioni E, Koh HC, Son IH. Paraquat activates the IRE1/ASK1/JNK cascade associated with apoptosis in human neuroblastoma SH-SY5Y cells. Toxicol Lett. 2009;191(2–3):203–10 (PubMed PMID: 19735704).

    CAS  PubMed  Google Scholar 

  210. Niso-Santano M, Bravo-San Pedro JM, Gomez-Sanchez R, Climent V, Soler G, Fuentes JM, et al. ASK1 overexpression accelerates paraquat-induced autophagy via endoplasmic reticulum stress. Toxicol Sci. 2011;119(1):156–68 (PubMed PMID: 20929985).

    CAS  PubMed  Google Scholar 

  211. Tsuboi Y. Environmental-genetic interactions in the pathogenesis of Parkinson’s disease. Exp Neurobiol. 2012;21(3):123–8 (PubMed PMID: 23055790. Pubmed Central PMCID: 3454809).

    PubMed Central  PubMed  Google Scholar 

  212. Goldman SM, Kamel F, Ross GW, Bhudhikanok GS, Hoppin JA, Korell M, et al. Genetic modification of the association of paraquat and Parkinson’s disease. Mov Disord. 2012;27(13):1652–8 (PubMed PMID: 23045187. Pubmed Central PMCID: 3572192).

    PubMed Central  CAS  PubMed  Google Scholar 

  213. Gonzalez-Polo R, Niso-Santano M, Moran JM, Ortiz-Ortiz MA, Bravo-San Pedro JM, Soler G, et al. Silencing DJ-1 reveals its contribution in paraquat-induced autophagy. J Neurochem. 2009;109(3):889–98 (PubMed PMID: 19425177).

    CAS  PubMed  Google Scholar 

  214. Bingol B, Tea JS, Phu L, Reichelt M, Bakalarski CE, Song Q, et al. The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature. 2014;510(7505):370–5 (PubMed PMID: 24896179).

    CAS  PubMed  Google Scholar 

  215. Kanthasamy A, Jin H, Anantharam V, Sondarva G, Rangasamy V, Rana A, et al. Emerging neurotoxic mechanisms in environmental factors-induced neurodegeneration. Neurotoxicology. 2012;33(4):833–7 (PubMed PMID: 22342404. Pubmed Central PMCID: 3377824).

    PubMed Central  PubMed  Google Scholar 

  216. Kanthasamy A, Anantharam V, Ali SF, Kanthasamy AG. Methamphetamine induces autophagy and apoptosis in a mesencephalic dopaminergic neuronal culture model: role of cathepsin-D in methamphetamine-induced apoptotic cell death. Ann N Y Acad Sci. 2006;1074:234–44 (PubMed PMID: 17105920).

    CAS  PubMed  Google Scholar 

  217. Abbott RD, Ross GW, White LR, Sanderson WT, Burchfiel CM, Kashon M, et al. Environmental, life-style, and physical precursors of clinical Parkinson’s disease: recent findings from the Honolulu-Asia Aging Study. J Neurol. 2003;250(Suppl 3):III30–9 (PubMed PMID: 14579122).

    PubMed  Google Scholar 

  218. Le Couteur DG Muller M Yang MC Mellick GD McLean AJ. Age-environment and gene-environment interactions in the pathogenesis of Parkinson’s disease. Rev Environ Health. 2002;17(1):51–64 (PubMed PMID: 12088093).

    PubMed  Google Scholar 

  219. Zorzon M, Capus L, Pellegrino A, Cazzato G, Zivadinov R. Familial and environmental risk factors in Parkinson’s disease: a case-control study in north-east Italy. Acta Neurol Scand. 2002;105(2):77–82 (PubMed PMID: 11903115).

    CAS  PubMed  Google Scholar 

  220. Martinez TN, Greenamyre JT. Toxin models of mitochondrial dysfunction in Parkinson’s disease. Antioxid Redox Signal. 2012;16(9):920–34 (PubMed PMID: 21554057. Pubmed Central PMCID: 3292753).

    PubMed Central  CAS  PubMed  Google Scholar 

  221. Ojha A, Yaduvanshi SK, Srivastava N. Effect of combined exposure of commonly used organophosphate pesticides on lipid peroxidation and antioxidant enzymes in rat tissues. Pestic Biochem Phys. 2011;99(2):148–56 (PubMed PMID: WOS:000286961500004. English).

    CAS  Google Scholar 

  222. Sharma H, Zhang P, Barber DS, Liu B. Organochlorine pesticides dieldrin and lindane induce cooperative toxicity in dopaminergic neurons: role of oxidative stress. Neurotoxicology. 2010;31(2):215–22 (PubMed PMID: 20036686).

    CAS  PubMed  Google Scholar 

  223. Chinta SJ, Andersen JK. Redox imbalance in Parkinson’s disease. Biochim Biophys Acta. 2008;1780(11):1362–7 (PubMed PMID: 18358848. Pubmed Central PMCID: 2547405).

    PubMed Central  CAS  PubMed  Google Scholar 

  224. Le W. Role of iron in UPS impairment model of Parkinson’s disease. Parkinsonism Relat Disord. 2014;20(Suppl 1):S158–61 (PubMed PMID: 24262171).

    PubMed  Google Scholar 

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Acknowledgments

This study was supported by grants from the National Institute of Health NS65167 and NS78247 and ES10586.

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Authors and Affiliations

  1. Parkinson’s Disorder Research Laboratory, Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, College of Veterinary Medicine, Iowa State University, 1600 S. 16th Street, 2024, 50011, Ames, IA, USA

    Neeraj Singh, Vivek Lawana, Niranjana Krishnan, Sri Harsha Kanuri, Huajun Jin, Vellareddy Anantharam, Anumantha Kanthasamy & Arthi Kanthasamy

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  1. Neeraj Singh
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  1. Bioquímica y Biología Molecular y Gen., Facultad de Enfermería y T.O., Cáceres, Spain

    José M. Fuentes

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Singh, N. et al. (2015). Agrochemicals-Induced Dopaminergic Neurotoxicity: Role of Mitochondria-Mediated Oxidative Stress and Protein Clearance Mechanisms. In: Fuentes, J. (eds) Toxicity and Autophagy in Neurodegenerative Disorders. Current Topics in Neurotoxicity, vol 9. Springer, Cham. https://doi.org/10.1007/978-3-319-13939-5_10

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