Skip to main content
SpringerLink
Log in

Localization of neuroglobin in the brain of R6/2 mouse model of Huntington’s disease

  • Original Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

Neuroglobin (Ngb) is expressed in the central and peripheral nervous system, cerebrospinal fluid, retina, and endocrine tissues where it is involved in binding O2 and other gasotransmitters. Several studies have highlighted its endogenous neuroprotective function. Huntington’s disease (HD), a dominant hereditary disease, is characterized by the gradual loss of neurons in discrete areas of the central nervous system. We analyzed the expression of Ngb in the brain tissue of a mouse model of HD, in order to define the role of Ngb with respect to individual cell type vulnerability in HD and to gender and age of mice. Our results showed different expressions of Ngb among neurons of a specific region and between different brain regions. We evidenced a decreased intensity of Ngb at 13 weeks of age, compared to 7 weeks of age. The double immunofluorescence and fluorescence resonance energy transfer (FRET) experiments showed that the co-localization between Ngb and huntingtin at the subcellular level was not close enough to account for a direct interaction. We also observed a different expression of Ngb in the striatum, depending on the sex and age of animals. These findings provide the first experimental evidence for an adaptive response of Ngb in HD, suggesting that Ngb may exert neuroprotective effects in HD beyond its role in reducing sensitivity to oxidative stress.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Albin RL, Tagle DA (1995) Genetics and molecular biology of Huntington’s disease. Trends Neurosci 18:11–14. https://doi.org/10.1016/0166-2236(95)93943-R

    Article  CAS  PubMed  Google Scholar 

  2. European Community Huntington’s Disease Collaborative Study Group (1993) Ethical and social issues in presymptomatic testing for Huntington’s disease: a European Community collaborative study. J Med Genet 30:1028–1035. https://doi.org/10.1136/jmg.30.12.1028

  3. Melone MA, Jori FP, Peluso G (2005) Huntington’s disease: new frontiers for molecular and cell therapy. Curr Drug Targets 6:43–56. https://doi.org/10.2174/1389450053344975

    Article  CAS  PubMed  Google Scholar 

  4. Perrone L, Melone MA (2008) New targets for therapy in polyglutamine (polyQ) expansion diseases. Curr Drug Ther 3:177–189. https://doi.org/10.2174/157488508785747835

    Article  CAS  Google Scholar 

  5. Leuti A, Laurenti D, Giampà C, Montagna E, Dato C, Anzilotti S, Melone MA, Bernardi G, Fusco FR (2013) Phosphodiesterase 10A (PDE10A) localization in the R6/2 mouse model of Huntington’s disease. Neurobiol Dis 52:104–116. https://doi.org/10.1016/j.nbd.2012.11.016

    Article  CAS  PubMed  Google Scholar 

  6. Vidoni C, Secomandi E, Castiglioni A, Melone MAB, Isidoro C (2017) Resveratrol protects neuronal-like cells expressing mutant huntingtin from dopamine toxicity by rescuing ATG4-mediated autophagosome formation. Neurochem Int [Epub ahead of print]. https://doi.org/10.1016/j.neuint.2017.05.013

  7. Ascenzi P, di Masi A, Leboffe L, Fiocchetti M, Nuzzo MT, Brunori M, Marino M (2016) Neuroglobin: from structure to function in health and disease. Mol Aspects Med 52:1–48. https://doi.org/10.1016/j.mam.2016.10.004

    Article  CAS  PubMed  Google Scholar 

  8. Brittain T (2012) The anti-apoptotic role of neuroglobin. Cell 1:1133–1155. https://doi.org/10.3390/cells1041133

    Article  CAS  Google Scholar 

  9. Khan AA, Mao XO, Banwait S, Jin K, Greenberg DA (2007) Neuroglobin attenuates beta-amyloid neurotoxicity in vitro and transgenic Alzheimer phenotype in vivo. Proc Natl Acad Sci U S A 104:19114–19119. https://doi.org/10.1073/pnas.0706167104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Greenberg DA, Jin K, Khan AA (2008) Neuroglobin: an endogenous neuroprotectant. Curr Opin Pharmacol 8:20–24. https://doi.org/10.1016/j.coph.2007.09.003

    Article  CAS  PubMed  Google Scholar 

  11. Jin K, Mao XO, Xie L, Khan AA, Greenberg DA (2008) Neuroglobin protects against nitric oxide toxicity. Neurosci Lett 430:135–137. https://doi.org/10.1016/j.neulet.2007.10.031

    Article  CAS  PubMed  Google Scholar 

  12. Wang X, Liu J, Zhu H, Tejima E, Tsuji K, Murata Y, Atochin DN, Huang PL, Zhang C, Lo EH (2008) Effects of neuroglobin overexpression on acute brain injury and long-term outcomes after focal cerebral ischemia. Stroke 39:1869–1874. https://doi.org/10.1161/STROKEAHA.107.506022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yu Z, Liu J, Guo S, Xing C, Fan X, Ning M, Yuan JC, Lo EH, Wang X (2009) Neuroglobin-overexpression alters hypoxic response gene expression in primary neuron culture following oxygen glucose deprivation. Neuroscience 162:396–403. https://doi.org/10.1016/j.neuroscience.2009.04.055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Carvalho C, Correia SC, Cardoso S, Placido AI, Candeias E, Duarte AI, Moreira PI (2015) The role of mitochondrial disturbances in Alzheimer, Parkinson and Huntington diseases. Expert Rev Neurother 15:867–884. https://doi.org/10.1586/14737175.2015.1058160

    Article  CAS  PubMed  Google Scholar 

  15. Nuzzo MT, Fiocchetti M, Totta P, Melone MA, Cardinale A, Fusco FR, Gustincich S, Persichetti F, Ascenzi P, Marino M (2016) Huntingtin polyQ mutation impairs the 17beta-estradiol/neuroglobin pathway devoted to neuron survival. Mol Neurobiol [Epub ahead of print]. https://doi.org/10.1007/s12035-016-0337-x

  16. Wystub S, Laufs T, Schmidt M, Burmester T, Maas U, Saaler-Reinhardt S, Hankeln T, Reuss S (2003) Localization of neuroglobin protein in the mouse brain. Neurosci Lett 346:114–116. https://doi.org/10.1016/S0304-3940(03)00563-9

    Article  CAS  PubMed  Google Scholar 

  17. Franklin KBJ, Paxinos G (2007) The mouse brain in stereotaxic coordinates. 3rd ed. trove.nla.gov.au/work/9674709

  18. Fusco FR, Martorana A, Giampa C, De March Z, Farini D, D'Angelo V, Sancesario G, Bernardi G (2004) Immunolocalization of CB1 receptor in rat striatal neurons: a confocal microscopy study. Synapse 53:159–167. https://doi.org/10.1002/syn.20047

    Article  CAS  PubMed  Google Scholar 

  19. Fusco FR, Zuccato C, Tartari M, Martorana A, De March Z, Giampa C, Cattaneo E, Bernardi G (2003) Co-localization of brain-derived neurotrophic factor (BDNF) and wild-type huntingtin in normal and quinolinic acid-lesioned rat brain. Eur J Neurosci 18:1093–1102. https://doi.org/10.1046/j.1460-9568.2003.02844.x

    Article  PubMed  Google Scholar 

  20. Amoroso MR, Matassa DS, Laudiero G, Egorova AV, Polishchuk RS, Maddalena F, Piscazzi A, Paladino S, Sarnataro D, Garbi C, Landriscina M, Esposito F (2012) TRAP1 and the proteasome regulatory particle TBP7/Rpt3 interact in the endoplasmic reticulum and control cellular ubiquitination of specific mitochondrial proteins. Cell Death Differ 19:592–604. https://doi.org/10.1038/cdd.2011.128

    Article  CAS  PubMed  Google Scholar 

  21. French AP, Mills S, Swarup R, Bennett MJ, Pridmore TP (2008) Colocalization of fluorescent markers in confocal microscope images of plant cells. Nat Protoc 3:619–628. https://doi.org/10.1038/nprot.2008.31

    Article  CAS  PubMed  Google Scholar 

  22. Albin RL, Reiner A, Anderson KD, Dure LST, Handelin B, Balfour R, Whetsell WO Jr, Penney JB, Young AB (1992) Preferential loss of striato-external pallidal projection neurons in presymptomatic Huntington’s disease. Ann Neurol 31:425–430. https://doi.org/10.1002/ana.410310412

    Article  CAS  PubMed  Google Scholar 

  23. Albin RL, Young AB, Penney JB, Handelin B, Balfour R, Anderson KD, Markel DS, Tourtellotte WW, Reiner A (1990) Abnormalities of striatal projection neurons and N-methyl-D-aspartate receptors in presymptomatic Huntington’s disease. N Engl J Med 322:1293–1298. https://doi.org/10.1056/NEJM199005033221807

    Article  CAS  PubMed  Google Scholar 

  24. Bolam JP, Hanley JJ, Booth PA, Bevan MD (2000) Synaptic organisation of the basal ganglia. J Anat 196(Pt 4):527–542. https://doi.org/10.1046/j.1469-7580.2000.19640527.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Vonsattel JP, Keller C, Cortes Ramirez EP (2011) Huntington’s disease—neuropathology. Handb Clin Neurol 100:83–100. https://doi.org/10.1016/B978-0-444-52014-2.00004-5

    Article  PubMed  Google Scholar 

  26. Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, MacDonald ME, Friedlander RM, Silani V, Hayden MR, Timmusk T, Sipione S, Cattaneo E (2001) Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science 293:493–498. https://doi.org/10.1126/science.1059581

    Article  CAS  PubMed  Google Scholar 

  27. Liu J, Yu Z, Guo S, Lee SR, Xing C, Zhang C, Gao Y, Nicholls DG, Lo EH, Wang X (2009) Effects of neuroglobin overexpression on mitochondrial function and oxidative stress following hypoxia/reoxygenation in cultured neurons. J Neurosci Res 87:164–170. https://doi.org/10.1002/jnr.21826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Papalexi E, Persson A, Bjorkqvist M, Petersen A, Woodman B, Bates GP, Sundler F, Mulder H, Brundin P, Popovic N (2005) Reduction of GnRH and infertility in the R6/2 mouse model of Huntington’s disease. Eur J Neurosci 22:1541–1546. https://doi.org/10.1002/jnr.21826

    Article  PubMed  Google Scholar 

  29. Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, Bates GP (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87:493–506. https://doi.org/10.1016/S0092-8674(00)81369-0

    Article  CAS  PubMed  Google Scholar 

  30. De Marinis E, Ascenzi P, Pellegrini M, Galluzzo P, Bulzomi P, Arevalo MA, Garcia-Segura LM, Marino M (2010) 17β-estradiol—a new modulator of neuroglobin levels in neurons: role in neuroprotection against H2O2-induced toxicity. Neurosignals 18:223–235. https://doi.org/10.1159/000323906

    Article  PubMed  Google Scholar 

  31. De Marinis E, Fiocchetti M, Acconcia F, Ascenzi P, Marino M (2013) Neuroglobin upregulation induced by 17β-estradiol sequesters cytocrome c in the mitochondria preventing H2O2-induced apoptosis of neuroblastoma cells. Cell Death Dis 4:e508. https://doi.org/10.1038/cddis.2013.30

    Article  PubMed  PubMed Central  Google Scholar 

  32. Sun Y, Jin K, Mao XO, Xie L, Peel A, Childs JT, Logvinova A, Wang X, Greenberg DA (2005) Effect of aging on neuroglobin expression in rodent brain. Neurobiol Aging 26:275–278. https://doi.org/10.1016/j.neurobiolaging.2004.03.006

    Article  CAS  PubMed  Google Scholar 

  33. Szymanski M, Wang R, Fallin MD, Bassett SS, Avramopoulos D (2010) Neuroglobin and Alzheimer’s dementia: genetic association and gene expression changes. Neurobiol Aging 31:1835–1842. https://doi.org/10.1016/j.neurobiolaging.2008.10.003

    Article  CAS  PubMed  Google Scholar 

  34. Zuccato C, Valenza M, Cattaneo E (2010) Molecular mechanisms and potential therapeutical targets in Huntington’s disease. Physiol Rev 90:905–981. https://doi.org/10.1152/physrev.00041.2009

    Article  CAS  PubMed  Google Scholar 

  35. Browne SE (2008) Mitochondria and Huntington’s disease pathogenesis: insight from genetic and chemical models. Ann N Y Acad Sci 1147:358–382. https://doi.org/10.1196/annals.1427.018

    Article  CAS  PubMed  Google Scholar 

  36. Yu Z, Liu N, Li Y, Xu J, Wang X (2013) Neuroglobin overexpression inhibits oxygen-glucose deprivation-induced mitochondrial permeability transition pore opening in primary cultured mouse cortical neurons. Neurobiol Dis 56:95–103. https://doi.org/10.1016/j.nbd.2013.04.015

    Article  CAS  PubMed  Google Scholar 

  37. Quintanilla RA, Tapia C, Perez MJ (2017) Possible role of mitochondrial permeability transition pore in the pathogenesis of Huntington disease. Biochem Biophys Res Commun 483:1078–1083. https://doi.org/10.1016/j.bbrc.2016.09.054

    Article  CAS  PubMed  Google Scholar 

  38. Sun F, Mao X, Xie L, Greenberg DA, Jin K (2013) Neuroglobin protein is upregulated in Alzheimer’s disease. J Alzheimers Dis 36:659–663. https://doi.org/10.3233/JAD-130323

    CAS  PubMed  Google Scholar 

  39. Raychaudhuri S, Skommer J, Henty K, Birch N, Brittain T (2010) Neuroglobin protects nerve cells from apoptosis by inhibiting the intrinsic pathway of cell death. Apoptosis 15:401–411. https://doi.org/10.1007/s10495-009-0436-5

    Article  CAS  PubMed  Google Scholar 

  40. Fordel E, Thijs L, Martinet W, Lenjou M, Laufs T, Van Bockstaele D, Moens L, Dewilde S (2006) Neuroglobin and cytoglobin overexpression protects human SH-SY5Y neuroblastoma cells against oxidative stress-induced cell death. Neurosci Lett 410:146–151. https://doi.org/10.1016/j.neulet.2006.09.027

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the animal facility of the IRCCS Fondazione Santa Lucia/EBRI/CNR.

Funding

This research was supported by a grant from the Ministry of Education, Universities and Research (MIUR) (Italy) under PRIN contract #20109MXHMR_004 (to MABM), for which the authors are indebted.

Author information

Author notes

  1. A. Cardinale and F. R. Fusco equally contributed to the manuscript.

Authors and Affiliations

  1. Department of Science, Roma Tre University, Rome, Italy

    A. Cardinale, M. Marino & M. T. Nuzzo

  2. Santa Lucia Foundation IRCCS, Rome, Italy

    A. Cardinale, F. R. Fusco, E. Paldino, C. Giampà & D. Laurenti

  3. Catholic University of Rome “Università Cattolica del Sacro Cuore”, Rome, Italy

    C. Giampà

  4. Department of Neuroscience, University of Rome Tor Vergata, Rome, Italy

    V. D’Angelo

  5. 2nd Division of Neurology and Center for Rare Diseases, Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Campania Luigi Vanvitelli, Naples, Italy

    G. Straccia, T. Squillaro & Mariarosa A. B. Melone

  6. Department of Molecular Medicine and Medical Biotechnology, Federico II University, Naples, Italy

    D. Fasano, D. Sarnataro & S. Paladino

  7. CEINGE Advanced Biotechnologies, Naples, Italy

    D. Sarnataro & S. Paladino

  8. InterUniversity Center for Research in Neurosciences, University of Campania Luigi Vanvitelli, Naples, Italy

    T. Squillaro & Mariarosa A. B. Melone

  9. Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, USA

    Mariarosa A. B. Melone

Authors
  1. A. Cardinale
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F. R. Fusco
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. Paldino
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. Giampà
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Marino
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. T. Nuzzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. V. D’Angelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D. Laurenti
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. G. Straccia
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. D. Fasano
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. D. Sarnataro
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. T. Squillaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. S. Paladino
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Mariarosa A. B. Melone
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mariarosa A. B. Melone.

Ethics declarations

All experiments were carried out in accordance with the Guide for the Care and Use of Laboratory Animals and the European Communities Council Directive of 24 November 1986 (86/609/EEC) as adopted by the Santa Lucia Foundation Animal Care and Use committee. The Santa Lucia Foundation Animal Care and Use committee specifically approved this study.

Conflict of interest

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cardinale, A., Fusco, F.R., Paldino, E. et al. Localization of neuroglobin in the brain of R6/2 mouse model of Huntington’s disease. Neurol Sci 39, 275–285 (2018). https://doi.org/10.1007/s10072-017-3168-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10072-017-3168-2

Keywords

Search

Navigation