Skip to main content

Advertisement

SpringerLink
Log in

Chaperone Hsp70 Content in Dopaminergic Neurons of the Substantia Nigra Increases in Proteasome Dysfunction

  • Published:
Neuroscience and Behavioral Physiology Aims and scope Submit manuscript

Decreases in the activity of the ubiquitin-proteasome system (UPS), which uses up to 90% of cell protein, are regarded as a key mechanism in the development of age-related conformational diseases (Parkinson’s disease (PD), Alzheimer’s disease, and others). Studies in a model of the preclinical stage of PD in Wistar rats showed that the specific UPS inhibitor lactacystin induced degeneration of 24% of dopaminergic neurons in the compact zone of the substantia nigra (czSN), which was almost the same as the proportion of neurons (23%) which in control conditions did not contain the chaperone 70-kDal Heat Shock Protein (Hsp70), which has neuroprotective properties. Of the 77% of neurons which contained Hsp70 in control conditions, 15% lost it in response to lactacystin (which may reduce their resistance to neurotoxin). However, 62% of surviving dopaminergic neurons in the czSN showed a 47% increase in Hsp70 content (which may protect them from degeneration). The increase in Hsp70 content (in czSN tissue) was verified by immunoblotting. Confocal microscopy studies identified partial colocalization of Hsp70 with the key dopamine (DA) synthesis enzyme tyrosine hydroxylase. Thus, moderate weakening of UPS function in czSN, typical of this model of the preclinical stage of PD, was characterized by an increase in the activity of the chaperone system. It is suggested that this process is directed to restoring UPS activity and preserving the dopaminergic neuron population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. I. V. Ekimova, T. G. Komarova, L. E. Nitsinskaya, et al., “The effects of exogenous 70-kDal heat shock protein and quercetin on NMDAinduced convulsions,” Dokl. Akad. Nauk., 418, No. 5, 705–708 (2008).

    Google Scholar 

  2. K. V. Lapshina and I. V. Ekimova, “Studies of the protective effects of exogenous 70-kDal heat shock protein in a sleep deprivation model in the pigeon Columba livia,” Zh. Evolyuts. Biokhim. Fiziol., 46, No. 5, 387–394 (2010).

    CAS  Google Scholar 

  3. B. A. Margulis and I. V. Guzhova, “Stress proteins in eukaryotic cells,” Tsitologiya, 42, 323–342 (2000).

    CAS  Google Scholar 

  4. B. A. Margulis and I. V. Guzhova, “The double role of chaperones in the stress responses of cells and the whole body,” Tsitologiya, 51, No. 3, 219–228 (2009).

    CAS  Google Scholar 

  5. L. E. Nitsinskaya, I. V. Ekimova, I. V. Guzhova, et al., “Effects of quercetin on the severity of chemically induced convulsions and 70-kDal heat shock protein content in rat brain structures,” Ros. Fiziol. Zh. im. I. M. Sechenova, 96, No. 3, 283–292 (2010).

    CAS  Google Scholar 

  6. Yu. F. Pastukhov and I. V. Ekimova, “Molecular, cellular, and systemic mechanisms of the protective functions of 70-kDal heat shock protein,” Neironauki, 2, No. 2, 3–25 (2005).

    Google Scholar 

  7. Yu. F. Pastukhov, I. V. Ekimova, K. A. Khudik, and I. V. Guzhova, “70-kDal protein in the control of sleep and thermoregulation,” Zh. Evolyuts. Biokhim. Fiziol., 44, No. 1, 65–71 (2008).

    Google Scholar 

  8. Yu. F. Pastukhov, K. A. Khudik, and I. V. Ekimova, “Chaperones in the regulation and restoration of physiological functions,” Ros. Fiziol. Zh. im. I. M. Sechenova, 96, No. 7, 708–725 (2010).

    CAS  Google Scholar 

  9. Yu. F. Pastukhov, M. V. Chernyshev, I. V. Ekimova, et al., “Molecular mechanisms of the homeostasis of sleep and anxiety and concepts of their biophysical bases,” in: Sleep and Anxiety [in Russian], Southern Scientific Center, Russian Academy of Sciences, Rostovon-Don (2008), pp. 235–268.

    Google Scholar 

  10. Yu. F. Pastukhov and A. Yu. Chesnokova, “Alpha-synuclein in the pathogenesis of Parkinson’s and other neurodegenerative diseases,” in: Neurodegenerative Diseases: Basic and Applied Aspects [in Russian], Nauka, Moscow (2010), pp. 189–200.

    Google Scholar 

  11. Yu. F. Pastukhov, A. Yu. Chesnokova, A. A. Yakimchuk, et al., “Changes in sleep on degeneration of substantia nigra neurons induced by the proteasome inhibitor lactacystin,” Ros. Fiziol. Zh. im. I. M. Sechenova, 96, No. 12, 1190–1202 (2010).

    CAS  Google Scholar 

  12. A. V. Sorokin, E. R. Kim, and L. P. Ovchinnikov, “The proteasome system for degradation and processing of proteins,” Usp. Biol. Khimii, 49, 3–76 (2009).

    Google Scholar 

  13. M. V. Ugryumov, “Traditional and novel concepts of the pathogenesis, diagnosis, and treatment of neurodegenerative diseases,” in: Neurodegenerative Diseases: Basic and Applies Aspects [in Russian], Nauka, Moscow (2010), pp. 8–35.

    Google Scholar 

  14. V. G. Khaindrava, E. A. Kozina, V. G. Kucheryanu, et al., “Modeling of the preclinical and early clinical stages of Parkinson’s disease,” Zh. Nevrol. Psikhiat. im. S. S. Korsakova, No. 7, 41–47 (2010).

  15. T. B. Ahn and B. S. Jeon, “Protective role of heat shock and heat shock protein 70 in lactacystin-induced cell death both in the rat substantia nigra and PC12 cells,” Brain Res., 1087, 159–167 (2006).

    Article  PubMed  CAS  Google Scholar 

  16. R. Betarbet, R. M. Canet-Aviles, T. B. Sherer, et al., “Intersecting pathways to neurodegeneration in Parkinson’s disease: effects of the pesticide rotenone on DJ-1, alpha-synuclein, and the ubiquitin-proteasome system,” Neurobiol. Dis., 22, No. 2, 404–420 (2006).

    Article  PubMed  CAS  Google Scholar 

  17. H. Braak, E. Ghebremedhin, U. Rub, and K. Del Tredici, “Stages in the development of Parkinson’s disease-related pathology,” Cell. Tiss. Res., 318, 121–134 (2004).

    Article  Google Scholar 

  18. A. J. Caplan, “What is a co-chaperone?” Cell Stress Chaperones, 8, No. 2, 105–107 (2003).

    Article  PubMed  Google Scholar 

  19. M. S. Choy, M. J. Chen, J. Manikandan, et al., “Up-regulation of endoplasmic reticulum stress-related genes during the early phase of treatment of cultured cortical neurons by the proteasomal inhibitor lactacystin,” J. Cell. Physiol., 226, No. 2, 494–510 (2011).

    Article  PubMed  CAS  Google Scholar 

  20. C. Cook and L. Petrucelli, “A critical evaluation of the ubiquitin-proteasome system in Parkinson’s disease,” Biochem. Biophys. Acta 1792, No. 7, 664–675 (2009).

    Article  PubMed  CAS  Google Scholar 

  21. Q. Ding and J. N. Keller, “Proteasome inhibition in oxidative stress neurotoxicity: implications for heat shock proteins,” J. Neurochem., 77, No. 4, 1010–1017 (2001).

    Article  PubMed  CAS  Google Scholar 

  22. I. V. Ekimova, L. E. Nizinsksya, I. V. Romanova, et al., “Exogenous protein Hsp70 can penetrate into the brain structures and attenuate the severity of chemically-induced seizures,” J. Neurochem., 115, No. 4, 1035–1044 (2010).

    Article  PubMed  CAS  Google Scholar 

  23. R. J. Ellis and S. M. van der Vies, “Molecular chaperones,” Annu. Rev. Biochem., 60, 321–347 (1991).

    Article  PubMed  CAS  Google Scholar 

  24. G. Fenteany, R. F. Standaert,W. S. Lane, et al., “Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin,” Science, 268, No. 5211, 726–731 (1995).

    Article  PubMed  CAS  Google Scholar 

  25. J. Imai, H. Yashiroda, M. Maruya, et al., “Proteasomes and molecular chaperones: cellular machinery responsible for folding and destruction of unfolded proteins,” Cell Cycle, 2, No. 6, 585–590 (2003).

    Article  PubMed  CAS  Google Scholar 

  26. H. H. Kampinga, “Chaperones in preventing protein denaturation in living cells and protecting against cellular stress,” Hand. Exp. Pharmacol., 172, 1–42 (2006).

    Article  CAS  Google Scholar 

  27. G. A. Kustanova, A. N. Murashev, V. L. Karpov, et al., “Exogenous heat shock protein 70 mediates sepsis manifestations and decreases the mortality rate in rats,” Cell Stress Chaperones, 11, No. 3, 276–286 (2006).

    Article  PubMed  CAS  Google Scholar 

  28. U. K. Laemmli, “Cleavage of structural proteins during the assembly of the head of bacteriophage T4,” Nature, 227, 680–685 (1970).

    Article  PubMed  CAS  Google Scholar 

  29. W. C. Lee, H. C. Wen, C. P. Chang, et al., “Heat shock protein 72 overexpression protects against hyperthermia, circulatory shock, and cerebral ischemia during heatstroke,” J. Appl. Physiol., 100, No. 6, 2073–2082 (2006).

    Article  PubMed  CAS  Google Scholar 

  30. K. L. Lim and J. M. Tan, “Role of the ubiquitin proteasome system in Parkinson’s disease,” BMC Biochem., 8, No. 1, S13 (2007).

    Article  PubMed  Google Scholar 

  31. A. M. Mabb and M. D. Ehlers, “Ubiquitination in postsynaptic function and plasticity,” Annu. Rev. Cell. Dev. Biol., 26, 179–210 (2010).

    Article  PubMed  CAS  Google Scholar 

  32. M. P. Mattson and T. Magnus, “Ageing and neuronal vulnerability,” Nat. Rev. Neurosci., 7, No. 4, 278–294 (2006).

    Article  PubMed  CAS  Google Scholar 

  33. 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).

    Article  PubMed  CAS  Google Scholar 

  34. K. S. McNaught, R. Jnobaptiste, T. Jackson, and T. A. Jengelley, “The pattern of neuronal loss and survival may reflect differential expression of proteasome activators of Parkinson’s disease,” Synapse, 64, No. 3, 241–250 (2010).

    Article  PubMed  CAS  Google Scholar 

  35. R. I. Morimoto, M. P. Kline, D. N. Bimston, and J. J. Cotto, “The heat-shock response: regulation and function of heat shock proteins and molecular chaperones,” Essays Biochem., 32, 17–29 (1997).

    PubMed  CAS  Google Scholar 

  36. P. J. Muchowski and J. L. Wacker, “Modulation of neurodegeneration by molecular chaperones,” Nat. Rev. Neurosci., 6, No. 1, 11–22 (2005).

    Article  PubMed  CAS  Google Scholar 

  37. T. V. Novoselova, B. A. Margulis, S. S. Novoselov, et al., “Treatment with extracellular Hsp70 protein can reduce polyglutamate toxicity and aggregation,” J. Neurochem., 94, No. 3, 597–606 (2005).

    Article  PubMed  CAS  Google Scholar 

  38. G. Paxinos and C. Watson, The Rat Brain in Stereotaxic Coordinates, Academic Press, San Diego (1998).

    Google Scholar 

  39. S. Perez-Alvarez, M. E. Solesio, J. Manzanares, et al., “Lactacystin requires reactive oxygen species and Bax redistribution to induce mitochondria-mediated cell death,” Br. J. Pharmacol., 158, No. 4, 1121–1130 (2009).

    Article  PubMed  CAS  Google Scholar 

  40. A. Segref and T. Hoppe, “Think locally: control of ubiquitin-dependent protein degradation in neurons,” EMBO Rep., 10, No. 1, 44–50 (2009).

    Article  PubMed  CAS  Google Scholar 

  41. G. Turturici, G. Sconzo, and F. Geraci, “Hsp70 and its molecular role in nervous system diseases,” Biochem. Res. Int., 618, 127 (2011).

    Google Scholar 

  42. M. V. Ugrumov, V. G. Khaindrava, E. A. Kozina, et al., “Modeling of presymptomatic and symptomatic stages of parkinsonism in mice,” Neurosci., 181, 175–188 (2011).

    Article  CAS  Google Scholar 

  43. V. N. Uversky, “Neuropathology, biochemistry, and biophysics of α-synuclein aggregation,” J. Neurochem., 103, No. 1, 17–37 (2007).

    PubMed  CAS  Google Scholar 

  44. S. Wickner, M. R. Maurizi, and S. Gottesman, “Posttranslational quality control: folding, refolding, and degrading proteins,” Science, 286, No. 5446, 1888–1893 (1999).

    Article  PubMed  CAS  Google Scholar 

  45. E. H. Yew, N. S. Cheung, M. S. Choy, et al., “Proteasome inhibition by lactacystin in primary neuronal cells both potentially neuroprotective and proapoptotic transcriptional responses: a microarray analysis,” J. Neurochem., 94, No. 4, 943–956 105

  46. B.-Y. Zeng, A. D. Medhurst, M. Jackson, et al., “Proteasomal activity in brain differs between species and brain regions and changes with age,” Mech. Age. Dev., 126, 760–766 (2005).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 44 Torez Prospekt, 194223, St. Petersburg, Russia

    Yu. F. Pastukhov, I. V. Ekimova, I. V. Romanova & Z. E. Artyukhina

  2. Institute of Cytology, Russian Academy of Sciences, 4 Tikhoretskii Prospekt, 194064, St. Petersburg, Russia

    I. V. Guzhova

Authors
  1. Yu. F. Pastukhov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I. V. Ekimova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I. V. Guzhova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. I. V. Romanova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Z. E. Artyukhina
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yu. F. Pastukhov.

Additional information

Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 97, No. 7, pp. 649–660, July, 2011.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pastukhov, Y.F., Ekimova, I.V., Guzhova, I.V. et al. Chaperone Hsp70 Content in Dopaminergic Neurons of the Substantia Nigra Increases in Proteasome Dysfunction. Neurosci Behav Physi 43, 380–387 (2013). https://doi.org/10.1007/s11055-013-9744-x

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11055-013-9744-x

Keywords

Search

Navigation