Neuroscience and Behavioral Physiology

, Volume 49, Issue 5, pp 555–561 | Cite as

An Infection Hypothesis of Parkinson’s Disease

  • M. N. KarpenkoEmail author
  • Z. M. Muruzheva
  • N. S. Pestereva
  • I. V. Ekimova

Parkinson’s disease (PD) is a multifactorial progressive neurodegenerative disease characterized by predominant degeneration of dopaminergic neurons in the substantia nigra. Neuroinflammation is one of the key components of the pathogenesis of PD, though the mechanisms initiating the inflammatory process and the triggers launching the irreversible neuroinflammatory process in patients with PD thus far remain unstudied. The present review addresses the role of infection-related factors in the etiology of PD. We evaluate the question of whether PD is the result of prior viral or bacterial infections due to the action of endotoxins on brain cells initiating the development of the inflammatory process in the CNS. Some cellular and animal models of PD of the infection type are presented and the molecular mechanisms of the development of neuroinflammation and neurodegeneration in these models are laid out. The final part of the review contains an analysis of reports, including those from the authors of this review, on the creation of valid models of the clinical and preclinical stages of PD in animals based on the proteasome inhibitor lactacystin, a metabolite of the soil bacterium Streptomyces sp.


Parkinson’s disease neuroinflammation viruses bacteria lipopolysaccharide proteasome inhibitors lactacystin 


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  1. 1.
    E. I. Gusev, A. B. Gekht, G. R. Popov, et al., Parkinson’s Disease. Clinical Aspects, Diagnosis, and Treatment of Neurodegenerative Diseases: Basic and Applied Aspects, M. V. Ugryumov (ed.), Nauka, Moscow (2010), pp. 52–86.Google Scholar
  2. 2.
    I. V. Ekimova, D. V. Plaksina, K. V. Lapshina, et al., “Pathological and compensatory processes in a new model of the preclinical stage of Parkinson’s disease in rats,” Acta Naturae, Spec. Iss., No. 1, 50 (2016).Google Scholar
  3. 3.
    I. V. Ekimova, V. V. Simonova, M. A. Guzeev, et al., “Changes in sleep characteristics in a model of the preclinical stage of Parkinson’s disease in rats based on weakening of the activity of the ubiquitin-proteasome system of the brain,” Zh. Evolyuts. Biokhim. Fiziol., 52, No. 6, 413–422 (2016).Google Scholar
  4. 4.
    S. N. Illarioshkin, “The course of Parkinson’s disease and approaches to the early diagnosis,” in: Parkinson’s Disease and Motor Disorders. Guidelines for Doctors: Proc. 2nd Nat. Congress on Parkinson’s Disease and Motor Disorders, S. N. Illarioshkin and O. S. Levin (eds.), Moscow (2011), pp. 41–47.Google Scholar
  5. 5.
    I. V. Milyukhina, M. N. Karpenko, A. A. Timofeeva, et al., “The role of inflammation and the pathogenesis of Parkinson’s disease,” Nevrol. Zh., 18, No. 3, 51–55 (2013).Google Scholar
  6. 6.
    Yu. F. Pastukhov, “Changes in the characteristics of paradoxical sleep – an early sign of Parkinson’s disease,” Zh. Vyssh. Nerv. Deyat., 63, No. 1, 75–85 (2013).Google Scholar
  7. 7.
    Yu. F. Pastukhov, I. V. Ekimova, and A. V. Chesnokova, “Molecular mechanisms of the pathogenesis of Parkinson’s disease and the potentials of preventive therapy,” in: Neurodegenerative Diseases – from Genome to the Whole Body. Part I. Motor Function and its Regulation in Health and Pathology, M. V. Ugryumov (ed.), Nauchnyi Mir, Moscow (2014), pp. 316–355.Google Scholar
  8. 8.
    Yu. F. Pastukhov, V. V. Simonova, M. A. Guzeev, and I. V. Ekimova, “Molecular mechanisms of sleep impairment at the initial stage of neurodegeneration induced by proteasomal dysfunction,” Acta Naturae, Spec. Iss., No. 1, 52 (2016).Google Scholar
  9. 9.
    Yu. F. Pastukhov, V. V. Simonova, M. V. Chernyshev, et al., “Signs of sleep impairment and behavior signaling the initial stage of neurodegenerative in a model of Parkinson’s disease,” Zh. Evolyuts. Biokhim. Fiziol., 53, No. 5, 380–384 (2017).Google Scholar
  10. 10.
    Yu. F. Pastukhov and A. Yu. Chesnokova, “α-Synuclein in the pathogenesis of Parkinson’s disease and other neurodegenerative diseases,” in: Neurodegenerative Diseases: Basic and Applied Aspects, M. V. Ugryumov (ed.), Nauka, Moscow (2010).Google Scholar
  11. 11.
    Yu. F. Pastukhov, A. Yu. Chesnokova, A. A. Yakimchuk, et al., “Changes in sleep in degeneration of the substantia nigra induced by the proteasome inhibitor lactacystin,” Ros. Fiziol. Zh., 96, No. 12, 1190–1202 (2010).Google Scholar
  12. 12.
    D. V. Plaksina, I. V. Ekimova, M. N. Karpenko, and Yu. F. Pastukhov, “Assessment of the functional state of the nigrostrial system of the brain in an experimental model of the preclinical stage of Parkinson’s disease in rats,” Zh. Evolyuts. Biokhim. Fiziol., 53, No. 5, 370–374 (2017).Google Scholar
  13. 13.
    M. V. Ugryumov, “Translated, personalized, and prophylactic medicine as the basis for the battle with neurodegenerative diseases,” in: Neurodegenerative Diseases – from Genome to the Whole Body, Nauchnyi Mir, Moscow (2014), pp. 316–355.Google Scholar
  14. 14.
    H. H. Balfour, S. K. Dunmire, and K. A. Hogquist, “Infectious mononucleosis,” Clin. Transl. Immunology, 4, No. 2, 33 (2015).Google Scholar
  15. 15.
    L. L. Barnes, A. W. Capuano, A. E. Aiello, et al., “Cytomegalovirus infection and risk of Alzheimer disease in older black and white individuals,” J. Infect. Dis., 211, No. 2, 230–237 (2015).Google Scholar
  16. 16.
    E. Bentea, L. Verbruggen, and A. Massie, “The proteasome inhibition model of Parkinson’s disease,” J. Parkinsons Dis., 7, No. 1, 31–63 (2017).Google Scholar
  17. 17.
    H. Braak, E. Ghebremedhin, U. Rub, et al., “Stages in the development of Parkinson’s disease related pathology,” Cell Tissue Res., 318, No. 1, 121–134 (2004).Google Scholar
  18. 18.
    X. L. Bu, X. Wang, Y. Xiang, et al., “The association between infectious burden and Parkinson’s disease: a case-control study,” Parkinsonism Relat. Disord., 21, No. 8, 877–881 (2015).Google Scholar
  19. 19.
    A. Cagnin, M. Kassiou, S. R. Meikle, and R. B. Banati, “Positron emission tomography imaging of neuroinflammation,” Neurotherapeutics, 4, No. 3, 443–452 (2007).Google Scholar
  20. 20.
    G. Çamci and S. Oğuz, “Association between Parkinson’s disease and Helicobacter pylori,” J. Clin. Neurology, 12, No. 2, 147–150 (2016).Google Scholar
  21. 21.
    P. M. Carvey, Q. Chang, J. W. Lipton, and Z. Ling, “Prenatal exposure to the bacteriotoxin lipopolysaccharide leads to long-term losses of dopamine neurons in offspring: a potential, new model of Parkinson’s disease,” Front. Biosci., 8, 826–837 (2003).Google Scholar
  22. 22.
    A. Castano, A. J. Herrera, J. Cano, and A. Machado, “Lipopolysaccharide intranigral injection induces inflammatory reaction and damage in nigrostriatal dopaminergic system,” J. Neurochem., 70, No. 4, 1584–1592 (1998).Google Scholar
  23. 23.
    G. Chapman, B. L. Beaman, D. A. Loeffler, et al., “In situ hybridization for detection of nocardial 16S rRNA: reactivity within intracellular inclusions in experimentally infected cynomolgus monkeys – and in Lewy body-containing human brain specimens,” Exp. Neurol., 184, No. 2, 715–725 (2003).Google Scholar
  24. 24.
    A. Charlett, R. J. Dobbs, S. M. Dobbs, et al., “Parkinsonism: siblings share Helicobacter pylori seropositivity and facets of syndrome,” Acta Neurol. Scand., 99, No. 1, 26–35 (1999).Google Scholar
  25. 25.
    A. Ciechanover and Y. T. Kwon, “Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies,” Exp. Mol. Med., 47, No. 3, е147 (2015).Google Scholar
  26. 26.
    T. Cross, “Aquatic actinomycetes: A critical survey of the occurrence, growth and role of actinomycetes in aquatic habitats,” J. Appl. Bacteriol., 50, No. 3, 397–423 (1981).Google Scholar
  27. 27.
    G. Deretzi, J. Kountouras, S. A. Polyzos, et al., “Gastrointestinal immune system and brain dialogue implicated in neuroinflammatory and neurodegenerative diseases,” Curr. Mol. Med., 11, No. 8, 696–707 (2011).Google Scholar
  28. 28.
    D. T. Dexter and P. Jenner, “Parkinson disease: From pathology to molecular disease mechanisms,” Free Radic. Biol. Med., 62, 132–144 (2013).Google Scholar
  29. 29.
    S. M. Dobbs, R. J. Dobbs, C. Weller, and A. Charlett, “Link between Helicobacter pylori infection and idiopathic parkinsonism,” Med. Hypotheses, 55, No. 2, 93–98 (2000).Google Scholar
  30. 30.
    C. T. M. Dow, “M. paratuberculosis and Parkinson’s disease – is this a trigger,” Med. Hypotheses, 83, No. 6, 709–712 (2014).Google Scholar
  31. 31.
    D. Ebrahimi-Fakhari, L. Wahlster, and P. J. McLean, “Protein degradation pathways in Parkinson’s disease: curse or blessing,” Acta Neuropathol., 124, No. 2, 153–172 (2012).Google Scholar
  32. 32.
    F. Fang, K. Wirdefeldt, A. Jacks, et al., “CNS infections, sepsis and risk of Parkinson’s disease,” Int. J. Epidemiol., 41, No. 4, 1042–1049 (2012).Google Scholar
  33. 33.
    G. Fenteany and S. L. Schreiber, “Lactacystin, proteasome function, and cell fate,” J. Biol. Chem., 273, No. 15, 8545–8548 (1998).Google Scholar
  34. 34.
    F. Fornai, P. Lenzi, M. Gesi, et al., “Fine structure and biochemical mechanisms underlying nigrostriatal inclusions and cell death after proteasome inhibition,” J. Neurosci., 23, 8955–8966 (2003).Google Scholar
  35. 35.
    D. M. Forton, J. M. Allsop, I. J. Cox, et al., “A review of cognitive impairment and cerebral metabolite abnormalities in patients with hepatitis C infection,” AIDS, 19, 53–63 (2005).Google Scholar
  36. 36.
    H. M. Gao, J. Jiang, B. Wilson, et al., “Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: relevance to Parkinson’s disease,” J. Neurochem., 81, No. 6, 1285–1297 (2002).Google Scholar
  37. 37.
    D. A. Gayle, Z. Ling, C. Tong, et al., “Lipopolysaccharide (LPS)-induced dopamine cell loss in culture: roles of tumor necrosis factor-α, interleukin-1β, and nitric oxide,” Dev. Brain Res., 133, No. 1, 27–35 (2002).Google Scholar
  38. 38.
    C. H. Hawkes, K. Del Tredici, and H. Braak, “Parkinson’s disease: a dual-hit hypothesis,” Neuropathol. Appl. Neurobiol., 33, No. 6, 599–614 (2007).Google Scholar
  39. 39.
    N. M. Joseph, B. N. Harish, S. Sistla, et al., “Streptomyces bacteremia in a patient with actinomycotic mycetoma,” J. Infect. Dev. Ctries., 4, No. 4, 249–252 (2010).Google Scholar
  40. 40.
    H. S. Jung, M. M. Ehlers, H. Lombaard, et al., “Etiology of bacterial vaginosis and polymicrobial biofilm formation,” Crit. Rev. Microbiol., 30, 1–17 (2017).Google Scholar
  41. 41.
    N. Kadoguchi, H. Kimoto, R. Yano, et al., “Failure of acute administration with proteasome inhibitor to provide a model of Parkinson’s disease in mice,” Metab. Brain. Dis., 23, 147–154 (2008).Google Scholar
  42. 42.
    S. Kohbata, and K. Shimokawa, “Circulating antibody to Nocardia in the serum of patients with Parkinson’s disease,” Adv. Neurology, 60, 355–357 (1992).Google Scholar
  43. 43.
    J. Konieczny, A. Czarnecka, T. Lenda, et al., “Chronic L-DOPA treatment attenuates behavioral and biochemical deficits induced by unilateral lactacystin administration into the rat substantia nigra,” Behav. Brain Res., 261, 79–88 (2014).Google Scholar
  44. 44.
    S. J. Kwon, T. B. Ahn, M. Y. Yoon, and B. S. Jeon, “BV-2 stimulation by lactacystin results in a strong inflammatory reaction and apoptotic neuronal death in SH-SY5Y cells,” Brain Res., 1205, 116–121 (2008).Google Scholar
  45. 45.
    E. Lahner, B. Annibale, and G. Delle Fave, “Systematic review: Helicobacter pylori infection and impaired drug absorption,” Aliment. Pharmacol. Ther., 29, No. 4, 379–386 (2009).Google Scholar
  46. 46.
    E. Lahner, C. Virili, M. G. Santaguida, et al., “Helicobacter pylori infection and drugs malabsorption,” World J. Gastroenterol., 20, No. 30, 10331–10337 (2014).Google Scholar
  47. 47.
    T. Laskus, M. Radkowski, D. M. Adair, et al., “Emerging evidence of hepatitis C virus neuroinvasion,” AIDS, 19, 140–144 (2005).Google Scholar
  48. 48.
    H. J. Lee, S. M. Baek, D. H. Ho, et al., “Dopamine promotes formation and secretion of non-fibrillar alpha-synuclein oligomers,” Exp. Mol. Med., 43, 4, 216–222 (2011).Google Scholar
  49. 49.
    Z. Ling, D. A. Gayle, S. Y. Ma, et al., “In utero bacterial endotoxin exposure causes loss of tyrosine hydroxylase neurons in the postnatal rat midbrain,” Mov. Disord., 17, No. 1, 116–124 (2002).Google Scholar
  50. 50.
    D. A. Loeffler, D. M. Camp, S. Qu, et al., “Characterization of dopamine-depleting activity of Nocardia asteroides strain GUH-2 culture filtrate on PC12 cells,” Microb. Pathog., 37, No. 2, 73–85 (2004).Google Scholar
  51. 51.
    A. B. Manning-Bog, S. H. Reaney, V. P. Chou, et al., “Lack of nigrostriatal pathology in a rat model of proteasome inhibition,” Ann. Neurol., 60, No. 2, 256–260 (2006).Google Scholar
  52. 52.
    C. N. Martyn and C. Osmond, “Parkinson’s disease and the environment in early life,” J. Neurol. Sci, 132, No. 2, 201–206 (1995).Google Scholar
  53. 53.
    O. Marques and T. F. Outeiro, “Alpha-synuclein: from secretion to dysfunction and death,” Cell Death Dis., 3, e350 (2012).Google Scholar
  54. 54.
    B. N. Mathur, M. D. Neely, M. Dyllick-Brenzinger, et al., “Systemic administration of a proteasome inhibitor does not cause nigrostriatal dopamine degeneration,” Brain Res., 1168, 83–89 (2007).Google Scholar
  55. 55.
    R. M. McManus and M. T. Heneka, “Role of neuroinflammation in neurodegeneration: new insights,” Alzheimers Res. Ther., 9, No. 1, 14 (2017).Google Scholar
  56. 56.
    K. S. McNaught, L. M. Bjorklund, R. Belizaire, et al., “Proteasome inhibition causes nigral degeneration with inclusion bodies in rats,” Neuroreport, 13, No. 11, 1437–1441 (2002).Google Scholar
  57. 57.
    K. S. McNaught, R. Belizaire, O. Isacson, et al., “Altered proteasomal function in sporadic Parkinson’s disease,” Exp. Neurol., 179, No. 1, 38–46 (2003).Google Scholar
  58. 58.
    K. S. McNaught, D. P. Perl, A. L. Brownell, and C. W. Olanow, “Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson’s disease,” Ann. Neurol., 56, No. 1, 149–162 (2004).Google Scholar
  59. 59.
    J. J. Neher, U. Neniskyte, T. Hornik, and G. C. Brown, “Inhibition of UDP/P2Y6 purinergic signaling prevents phagocytosis of viable neurons by activated microglia in vitro and in vivo,” Glia, 62, No. 9, 1463–1475 (2014).Google Scholar
  60. 60.
    C. Niu, J. Me, Q. Pan, and X. Fu, “Nigral degeneration with inclusion body formation and behavioral changes in rats after proteasomal inhibition,” Stereotact. Funct. Neurosurg., 87, No. 2, 69–81 (2009).Google Scholar
  61. 61.
    C. Noelker, L. Morel, T. Lescot, et al., “Toll like receptor 4 mediates cell death in a mouse MPTP model of Parkinson disease,” Sci. Rep., 3, 1393 (2013).Google Scholar
  62. 62.
    A. Ogata, K. Tashiro, S. Nukuzuma, et al., “A rat model of Parkinson’s disease induced by Japanese encephalitis virus,” J. Neurovirol., 3, No. 2, 141–147 (1997).Google Scholar
  63. 63.
    E. Okun, K. J. Griffioen, and M. P. Mattson, “Toll-like receptor signaling in neural plasticity and disease,” Trends Neurosci., 34, No. 5, 269–281 (2011).Google Scholar
  64. 64.
    Y. Ouchi, T. Kanno, H. Okada, et al., “Presynaptic and postsynaptic dopaminergic binding densities in the nigrostriatal and mesocortical systems in early Parkinson’s disease: A double-tracer positron emission tomography study,” Ann. Neurol., 46, No. 5, 723–731 (1999).Google Scholar
  65. 65.
    Y. Ouchi, E. Yoshikawa, Y. Sekine, et al., “Microglial activation and dopamine terminal loss in early Parkinson’s disease,” Ann. Neurol., 57, No. 2, 168–175 (2005).Google Scholar
  66. 66.
    D. V. Plaksina, M. V. Chernyshev, M. N. Karpenko, et al., “Experimental modeling of a preclinical Parkinson’s disease stage in rats by intranasal lactacystin administration,” Neurodegen. Dis. (Suppl), 17, No. 1, 1655 (2017).Google Scholar
  67. 67.
    A. Priyadarshi, S. A. Khuder, E. A. Schaub, and S. S. Priyadarshi, “Environmental risk factors and Parkinson’s disease: a metaanalysis,” Environ. Res., 86, No. 2, 122–127 (2001).Google Scholar
  68. 68.
    S. Sadasivan, B. Sharp, S. Schultz-Cherry, and R. J. Smeyne, “Synergistic effects of influenza and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can be eliminated by the use of influenza therapeutics: experimental evidence for the multi-hit hypothesis,” Parkinson’s Dis., 3, No. 1, 18 (2017).Google Scholar
  69. 69.
    M. H. Savolainen, K. Albert, M. Airavaara, and T. T. Myohanen, “Nigral injection of a proteasomal inhibitor, lactacystin, induces widespread glial cell activation and shows various phenotypes of Parkinson’s disease in young and adult mouse,” Exp. Brain Res., 1–14 (2017).Google Scholar
  70. 70.
    A. H. Schapira, M. W. Cleeter, J. R. Muddle, et al., “Proteasomal inhibition causes loss of nigral tyrosine hydroxylase neurons,” Ann. Neurol., 60, No. 2, 253–255 (2006).Google Scholar
  71. 71.
    S. A. Staras, S. C. Dollard, K. W. Radford, et al., “Seroprevalence of cytomegalovirus infection in the United States, 1988–1994,” Clin. Infect. Dis., 43, No. 9, 1143–1151 (2006).Google Scholar
  72. 72.
    A. H. Tan, S. Mahadeva, C. Marras, et al., “Helicobacter pylori infection is associated with worse severity of Parkinson’s disease,” Parkinsonism Relat. Disord., 21, No. 3, 221–225 (2015).Google Scholar
  73. 73.
    H. Tomoda and S. Omura, “Lactacystin, a proteasome inhibitor: discovery and its application in cell biology,” Yakugaku Zasshi, 120, No. 10, 935–949 (2000).Google Scholar
  74. 74.
    S. Toovey, S. S. Jick, and C. R. Meier, “Parkinson’s disease or Parkinson symptoms following seasonal influenza,” Influenza Other Respir. Viruses, 5, No. 5, 328–333 (2011).Google Scholar
  75. 75.
    H. H. Tsai, H. H. Liou, C. H. Muo, et al., “Hepatitis C virus infection as a risk factor for Parkinson disease A nationwide cohort study,” Neurology, 86, No. 9, 840–846 (2016).Google Scholar
  76. 76.
    J. Y. Wang, J. Y. Wang, J. Y. Wang, et al., “Ethanol modulates induction of nitric oxide synthase in glial cells by endotoxin,” Life Sci., 63, No. 17, 1571–1583 (1998).Google Scholar
  77. 77.
    J. M. Woulfe, M. T. Gray, D. A. Gray, et al., “Hypothesis: a role for EBV-induced molecular mimicry in Parkinson’s disease,” Parkinsonism Relat. Disord., 20, No. 7, 685–694 (2014).Google Scholar
  78. 78.
    W. Y. Wu, K. H. Kang, S. S. Chen, et al., “Hepatitis C virus infection: a risk factor for Parkinson’s disease,” J. Viral. Hepat., 22, No. 10, 784–791 (2015).Google Scholar
  79. 79.
    B. Y. Zeng, S. Bukhatwa, A. Hikima, et al., “Reproducible nigral cell loss after systemic proteasomal inhibitor administration to rats,” Ann. Neurol., 60, No. 2, 248–252 (2006).Google Scholar

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Authors and Affiliations

  • M. N. Karpenko
    • 1
    • 2
    • 3
    • 4
    Email author
  • Z. M. Muruzheva
    • 2
  • N. S. Pestereva
    • 2
    • 3
  • I. V. Ekimova
    • 1
  1. 1.Sechenov Institute of Evolutionary Physiology and BiochemistryRussian Academy of SciencesSt. PetersburgRussia
  2. 2.Institute of Experimental MedicineSt. PetersburgRussia
  3. 3.Peter the Great St. Petersburg Polytechnic UniversitySt. PetersburgRussia
  4. 4.St. Petersburg National Research University for Information Technologies, Mechanics, and OpticsSt. PetersburgRussia

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