Skip to main content

Advertisement

SpringerLink
Log in

Huntingtin polyQ Mutation Impairs the 17β-Estradiol/Neuroglobin Pathway Devoted to Neuron Survival

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Among several mechanisms underlying the well-known trophic and protective effects of 17β-estradiol (E2) in the brain, we recently reported that E2 induces the up-regulation of two anti-apoptotic and neuroprotectant proteins: huntingtin (HTT) and neuroglobin (NGB). Here, we investigate the role of this up-regulation. The obtained results indicate that E2 promotes NGB-HTT association, induces the localization of the complex at the mitochondria, and protects SK-N-BE neuroblastoma cells and murine striatal cells, which express wild-type HTT (i.e., polyQ7), against H2O2-induced apoptosis. All E2 effects were completely abolished in HTT-knocked out SK-N-BE cells and in striatal neurons expressing the mutated form of HTT (mHTT; i.e., polyQ111) typical of Huntington’s disease (HD). As a whole, these data provide a new function of wild-type HTT which drives E2-induced NGB in mitochondria modulating NGB anti-apoptotic activity. This new function is lost by HTT polyQ pathological expansion. These data evidence the existence of a novel E2/HTT/NGB neuroprotective axis that may play a relevant role in the development of HD therapeutics.

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.
Fig. 6.
Fig. 7.

Similar content being viewed by others

Abbreviations

BSA:

Bovine serum albumin

DMEM:

Dulbecco’s modified Eagle medium

E2:

17β-Estradiol

ER:

Estrogen receptor

ERα:

Estrogen receptor α

ERβ:

Estrogen receptor β

HD:

Huntington’s disease

HTT:

Wild-type huntingtin

mHTT:

HTT mutant

NGB:

Neuroglobin

polyQ:

Polyglutamine

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

scRNA:

Scramble RNA

shHTT:

Short hairpin RNA for HTT

References

  1. Cattaneo E, Rigamonti D, Goffredo D, Zuccato C, Squitieri F, Sipione S (2001) Loss of normal huntingtin function: new developments in Huntington’s disease research. Trend Neurosci 24:182–188

    Article  CAS  PubMed  Google Scholar 

  2. Takano H, Gusella JF (2002) The predominantly HEAT-like motif structure of huntingtin and its association and coincident nuclear entry with dorsal, an NF-kB/Rel/dorsal family transcription factor. BMC Neurosci 3:15

    Article  PubMed  PubMed Central  Google Scholar 

  3. Palidwor GA, Shcherbinin S, Huska MR, Rasko T, Stelzl U, Arumughan A et al (2009) Detection of alpha-rod protein repeats using a neural network and application to huntingtin. PLoS Comput Biol 5:e1000304

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ochaba J, Lukacsovich T, Csikos G, Zheng S, Margulis J, Salazar L et al (2014) Potential function for the Huntingtin protein as a scaffold for selective autophagy. Proc Natl Acad Sci U S A 111:16889–16894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Rui YN, Xu Z, Patel B, Chen Z, Chen D, Tito A et al (2015) Huntingtin functions as a scaffold for selective macroautophagy. Nat Cell Biol 17:262–275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Xia J, Lee DH, Taylor J, Vandelft M, Truant R (2003) Huntingtin contains a highly conserved nuclear export signal. Human Mol Genet 12:1393–1403

    Article  CAS  Google Scholar 

  7. Li W, Serpell LC, Carter WJ, Rubinsztein DC, Huntington JA (2006) Expression and characterization of full-length huntingtin, an elongated HEAT repeat protein. J Biol Chem 281:15916–15922

    Article  CAS  PubMed  Google Scholar 

  8. Zuccato C, Valenza M, Cattaneo E (2010) Molecular mechanisms and potential therapeutic targets in Huntington’s disease. Physiol Rev 90:905–981

    Article  CAS  PubMed  Google Scholar 

  9. Saudou F, Humbert S (2016) The biology of huntingtin. Neuron 89:910–926

    Article  CAS  PubMed  Google Scholar 

  10. The Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983

    Article  Google Scholar 

  11. Ratovitski T, Chighladze E, Arbez N, Boronina T, Herbrich S, Cole RN et al (2012) Huntingtin protein interactions altered by polyglutamine expansion as determined by quantitative proteomic analysis. Cell Cycle 11:2006–2021

    Article  PubMed  PubMed Central  Google Scholar 

  12. Cattaneo E, Zuccato C, Tartari M (2005) Normal huntingtin function: an alternative approach to Huntington’s disease. Nature Rev Neurosci 6:919–930

    Article  CAS  Google Scholar 

  13. Borrell-Pagès M, Zala D, Humbert S, Saudou S (2006) Huntington’s disease: from huntingtin function and dysfunction to therapeutic strategies. Cellular and Molecular Life Sci 63:2642–2660

    Article  Google Scholar 

  14. Clabough EB (2013) Huntington’s disease: the past, present, and future search for disease modifiers. Yale J Biol Med 86:217–233

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Dragatsis I, Levine M, Zeitlin S (2000) Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nat Genet 26:300–306

    Article  CAS  PubMed  Google Scholar 

  16. Amantea D, Russo R, Bagetta G, Corasaniti MT (2005) From clinical evidence to molecular mechanisms underlying neuroprotection afforded by estrogens. Pharmacol Res 52:119–132

    Article  CAS  PubMed  Google Scholar 

  17. Barha CK, Galea LA (2010) Influence of different estrogens on neuroplasticity and cognition in the hippocampus. Biochim Biophys Acta 1800:1056–1067

    Article  CAS  PubMed  Google Scholar 

  18. Gillies GE, McArthur S (2010) Estrogen actions in the brain and the basis for differential action in men and women: a case for sex-specific medicines. Pharmacol Rev 62:155–198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fiocchetti M, Ascenzi P, Marino M (2012) Neuroprotective effects of 17β-estradiol rely on estrogen receptor membrane initiated signals. Front Physiol 3:e73

    Article  Google Scholar 

  20. Srivastava DP, Woolfrey KM, Penzes P (2013) Insights into rapid modulation of neuroplasticity by brain estrogens. Pharmacol Rev 65:1318–1350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. McEwen BS (2014) Sex, stress and the brain: interactive actions of hormones on the developing and adult brain. Climacteric 17:18–25

    Article  CAS  PubMed  Google Scholar 

  22. Arevalo MA, Azcoitia I, Garcia-Segura LM (2015) The neuroprotective actions of oestradiol and oestrogen receptors. Nature Rev Neurosci 16:17–29

    Article  CAS  Google Scholar 

  23. Bourque M, Morissette M, Di Paolo T (2015) Neuroprotection in Parkinsonian-treated mice via estrogen receptor α activation requires G protein-coupled estrogen receptor 1. Neuropharmacol 95:343–352

    Article  CAS  Google Scholar 

  24. Chisholm NC, Sohrabji F (2016) Astrocytic response to cerebral ischemia is influenced by sex differences and impaired by aging. Neurobiol Dis 85:245–253

    Article  CAS  PubMed  Google Scholar 

  25. Fester L, Rune GM (2015) Sexual neurosteroids and synaptic plasticity in the hippocampus. Brain Res 1621:162–169

    Article  CAS  PubMed  Google Scholar 

  26. Kunimura Y, Iwata K, Iijima N, Kobayashi M, Ozawa H (2015) Effect of sex steroid hormones on the number of serotonergic neurons in rat dorsal raphe nucleus. Neurosci Lett 594:127–132

    Article  CAS  PubMed  Google Scholar 

  27. Li R, Cui J, Shen Y (2014) Brain sex matters: estrogen in cognition and Alzheimer’s disease. Mol Cell Endocrinol 389:13–21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Naderi V, Khaksari M, Abbasi R, Maghool F (2015) Estrogen provides neuroprotection against brain edema and blood brain barrier disruption through both estrogen receptors α and β following traumatic brain injury. Iran J Basic Med Sci 18:138–144

    PubMed  PubMed Central  Google Scholar 

  29. Pietranera L, Brocca ME, Roig P, Lima A, Garcia-Segura LM, De Nicola AF (2014) Estrogens are neuroprotective factors for hypertensive encephalopathy. J Steroid Biochem Mol Biol 146:15–25

    Article  PubMed  Google Scholar 

  30. Sarkar S, Jun S, Simpkins JW (2015) Estrogen amelioration of Aβ-induced defects in mitochondria is mediated by mitochondrial signaling pathway involving ERβ, AKAP and Drp1. Brain Res 1616:101–111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Scott N, Prigge M, Yizhar O, Kimchi T (2015) A sexually dimorphic hypothalamic circuit controls maternal care and oxytocin secretion. Nature 525:519–522

    Article  CAS  PubMed  Google Scholar 

  32. Sellers KJ, Erli F, Raval P, Watson IA, Chen D, Srivastava DP (2015) Rapid modulation of synaptogenesis and spinogenesis by 17β-estradiol in primary cortical neurons. Front Cell Neurosci 9:137

    Article  PubMed  PubMed Central  Google Scholar 

  33. Uzum G, Bahçekapılı N, Baltaci AK, Mogulkoc R, Ziylan YZ (2015) Pre- and post-estrogen administration in global cerebral ischemia reduces blood-brain barrier breakdown in ovariectomized rats. Acta Physiol Hung 102:60–66

    Article  CAS  PubMed  Google Scholar 

  34. Xu P, Cao X, He Y, Zhu L, Yang Y, Saito K et al (2015) Estrogen receptor-α in medial amygdala neurons regulates body weight. J Clin Invest 125:2861–2876

    Article  PubMed  PubMed Central  Google Scholar 

  35. De Marinis E, Marino M, Ascenzi P (2011) Neuroglobin, estrogens, and neuroprotection. IUBMB Life 63:140–145

    Article  CAS  PubMed  Google Scholar 

  36. Asl SZ, Khaksari M, Khachki AS, Shahrokhi N, Nourizade S (2013) Contribution of estrogen receptors alpha and beta in the brain response to traumatic brain injury. J Neurosurg 119:353–361

    Article  PubMed  Google Scholar 

  37. Morissette M, Le Saux M, D'Astous M, Jourdain S, Al Sweidi S, Morin N et al (2008) Contribution of estrogen receptors alpha and beta to the effects of estradiol in the brain. J Steroid Biochem Mol Biol 108:327–338

    Article  CAS  PubMed  Google Scholar 

  38. Greenberg DA, Jin K, Khan AA (2008) Neuroglobin: an endogenous neuroprotectant. Curr Opin Pharmacol 8:20–24

    Article  CAS  PubMed  Google Scholar 

  39. Yu Z, Fan X, Lo EH, Wang X (2009) Neuroprotective roles and mechanisms of neuroglobin. Neurol Res 31:122–127

    Article  PubMed  PubMed Central  Google Scholar 

  40. De Marinis E, Ascenzi P, Pellegrini M, Galluzzo P, Bulzomi P, Arevalo MA et al (2010) 17β-estradiol-a new modulator of neuroglobin levels in neurons: role in neuroprotection against H2O2-induced toxicity. Neurosignals 18:223–235

    Article  CAS  PubMed  Google Scholar 

  41. Fiocchetti M, De Marinis E, Ascenzi P, Marino M (2013) Neuroglobin and neuronal cell survival. Biochim Biophys Acta 1834:1744–1749

    Article  CAS  PubMed  Google Scholar 

  42. Yu Z, Poppe JL, Wang X (2013) Mitochondrial mechanisms of neuroglobin’s neuroprotection. Oxidative Med Cell Longev 2013:756989

    Article  Google Scholar 

  43. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Nuzzo MT, Fiocchetti M, Ascenzi P, Marino M (2014) Neuroglobin and estrogen receptors: a new pathway of cell survival and cell death balance. Immun Endo Metabol Agents Med Chem 14:91–99

    Article  CAS  Google Scholar 

  45. Nuzzo MT, Fiocchetti M, Trezza V, Ascenzi P, Marino M (2016) Huntingtin up-regulation is necessary for 17-β-estradiol protective effects against oxidative stress injury in human neuroblastoma cell line. Neurosci Res 103:59–63

    Article  CAS  PubMed  Google Scholar 

  46. Luine VN (2014) Estradiol and cognitive function: past, present and future. Horm Behav 66:602–618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Murakami G, Hojo Y, Ogiue-Ikeda M, Mukai H, Chambon P, Nakajima K et al. (2014) Estrogen receptor KO mice study on rapid modulation of spines and long-term depression in the hippocampus. Brain Res

  48. Yoest KE, Cummings JA, Becker JB (2014) Estradiol, dopamine and motivation. Cent Nerv Syst Agent Med Chem 14:83–89

    Article  CAS  Google Scholar 

  49. Fusco FR, Anzilotti S, Giampà C, Dato C, Laurenti D, Leuti A et al (2012) Changes in the expression of extracellular regulated kinase (ERK 1/2) in the R6/2 mouse model of Huntington’s disease after phosphodiesterase IV inhibition. Neurobiol Dis 46:225–233

    Article  CAS  PubMed  Google Scholar 

  50. Trettel F, Rigamonti D, Hilditch-Maguire P, Wheeler VC, Sharp AH, Persichetti F et al (2000) Dominant phenotypes produced by the HD mutation in STHdh(Q111) striatal cells. Hum Mol Genet 9:2799–2809

    Article  CAS  PubMed  Google Scholar 

  51. Vonsattel JP, DiFiglia M (1998) Huntington disease. J Neuropathol Exp Neurol 57:369–384

    Article  CAS  PubMed  Google Scholar 

  52. Fiocchetti M, Nuzzo MT, Totta P, Acconcia F, Ascenzi P, Marino M (2014) Neuroglobin, a pro-survival player in estrogen receptor α-positive cancer cells. Cell Death Dis 5:e1449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Nguyen KQ, Rymar VV, Sadikot AF (2016) Impaired TrkB signaling underlies reduced BDNF-mediated trophic support of striatal neurons in the R6/2 mouse model of Huntington's disease. Front Cell Neurosci 10:37

    Article  PubMed  PubMed Central  Google Scholar 

  54. Giampà C, Montagna E, Dato C, Melone MA, Bernardi G, Fusco FR (2013) Systemic delivery of recombinant brain derived neurotrophic factor (BDNF) in the R6/2 mouse model of Huntington's disease. PLoS One 8:e64037

    Article  PubMed  PubMed Central  Google Scholar 

  55. Yu Z, Liu N, Wang Y, Li X, Wang X (2012) Identification of neuroglobin-interacting proteins using yeast two-hybrid screening. Neurosci 200:99–105

    Article  CAS  Google Scholar 

  56. Schmidt-Kastner R, Haberkamp M, Schmitz C, Hankeln T, Burmester T (2006) Neuroglobin mRNA expression after transient global brain ischemia and prolonged hypoxia in cell culture. Brain Res 1103:173–180

    Article  CAS  PubMed  Google Scholar 

  57. Ye SQ, Zhou XY, Lai XJ, Zheng L, Chen XQ (2009) Silencing neuroglobin enhances neuronal vulnerability to oxidative injury by down-regulating 14-3-3gamma. Acta Pharmacol Sin 30:913–918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Fordel E, Thijs L, Martinet W, Schrijvers D, Moens L, Dewilde S (2007) Anoxia or oxygen and glucose deprivation in SH-SY5Y cells: a step closer to the unraveling of neuroglobin and cytoglobin functions. Gene 398:114–122

    Article  CAS  PubMed  Google Scholar 

  59. Hundahl C, Kelsen J, Kjaer K, Ronn LC, Weber RE, Geuens E et al (2006) Does neuroglobin protect neurons from ischemic insult? A quantitative investigation of neuroglobin expression following transient MCAo in spontaneously hypertensive rats. Brain Res 1085:19–27

    Article  CAS  PubMed  Google Scholar 

  60. Khan AA, Wang Y, Sun Y, Mao XO, Xie L, Miles E et al (2006) Neuroglobin-overexpressing transgenic mice are resistant to cerebral and myocardial ischemia. Proc Natl Acad Sci U S A 103:17944–17948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Cai B, Lin Y, Xue XH, Fang L, Wang N, Wu ZY (2010) TAT-mediated delivery of neuroglobin protects against focal cerebral ischemia in mice. Exp Neurol 227:224–231

    Article  PubMed  Google Scholar 

  62. Li RC, Guo SZ, Lee SK, Gozal D (2010) Neuroglobin protects neurons against oxidative stress in global ischemia. J Cereb Blood Flow Metab 30:1874–1882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 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

    Article  CAS  PubMed  Google Scholar 

  64. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Fordel E, Thijs L, Martinet W, Lenjou M, Laufs T, Van Bockstaele D et al (2006) Neuroglobin and cytoglobin overexpression protects human SH-SY5Y neuroblastoma cells against oxidative stress-induced cell death. Neurosci Lett 410:146–151

    Article  CAS  PubMed  Google Scholar 

  66. 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

    Article  CAS  PubMed  Google Scholar 

  67. Fiocchetti M, Cipolletti M, Leone S, Naldini A, Carraro F, Giordano D et al (2016) Neuroglobin in breast cancer cells: effect of hypoxia and oxidative stress on protein level, localization, and anti-apoptotic function. PLoS One 11:e0154959

    Article  PubMed  PubMed Central  Google Scholar 

  68. Nuzzo MT, Marino M (2016) Estrogen/Huntingtin: a novel pathway involved in neuroprotection. Neural Regen Res 11:402–403

    Article  PubMed  PubMed Central  Google Scholar 

  69. Colin E, Régulier E, Perrin V, Dürr A, Brice A, Aebischer P et al (2005) Akt is altered in an animal model of Huntington’s disease and in patients. Eur J Neurosci 21:1478–1488

    Article  PubMed  Google Scholar 

  70. Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L et al (2001) Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science 293:493–498

    Article  CAS  PubMed  Google Scholar 

  71. Cutrupi S, Ferrero G, Reineri S, Cordero F, De Bortoli M (2014) Genomic lens on neuroglobin transcription. IUBMB Life 66:46–51

    Article  CAS  PubMed  Google Scholar 

  72. Li SH, Cheng AL, Zhou H, Lam S, Rao M, Li H et al (2002) Interaction of Huntington disease protein with transcriptional activator Sp1. Mol Cell Biol 22:1277–1287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Boutell JM, Thomas P, Neal JW, Weston VJ, Duce J, Harper PS et al (1999) Aberrant interactions of transcriptional repressor proteins with the Huntington’s disease gene product, huntingtin. Hum Mol Genet 8:1647–1655

    Article  CAS  PubMed  Google Scholar 

  74. Harjes P, Wanker EE (2003) The hunt for huntingtin function: interaction partners tell many different stories. Trends Biochem Sci 28:425–433

    Article  CAS  PubMed  Google Scholar 

  75. Li SH, Li XJ (2004) Huntingtin–protein interactions and the pathogenesis of Huntington’s disease. Trends Genet 20:146–154

    Article  PubMed  Google Scholar 

  76. Subramaniam S, Sixt KM, Barrow R, Snyder SH (2009) Rhes, a striatal specific protein, mediates mutant huntingtin cytotoxicity. Science 324:1327–1330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kaltenbach LS, Romero E, Becklin RR, Chettier R, Bell R, Phansalkar A et al (2007) Huntingtin interacting proteins are genetic modifiers of neurodegeneration. PLoS Genet 3:82

    Article  Google Scholar 

  78. Bode FJ, Stephan M, Suhling H, Pabst R, Straub RH, Raber KA et al (2008) Sex differences in a transgenic rat model of Huntington’s disease: decreased 17beta-estradiol levels correlate with reduced numbers of DARPP32+ neurons in males. Hum Mol Genet 17:2595–2609

    Article  CAS  PubMed  Google Scholar 

  79. Smith KM, Dahodwala N (2014) Sex differences in Parkinson’s disease and other movement disorders. Exp Neurol 259:44–56

    Article  CAS  PubMed  Google Scholar 

  80. Rigamonti D, Bauer JH, De-Fraja C, Conti L, Sipione S, Sciorati C et al (2000) Wild-type huntingtin protects from apoptosis upstream of caspase-3. J Neurosci 20:3705–3713

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from Associazione Italiana Ricerca sul Cancro (AIRC, IG#15221) to M.M. and from Ministero dell’Istruzione, dell’Università e della Ricerca of Italy (PRIN 20109MXHMR_001) to P.A.

Author information

Authors and Affiliations

  1. Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, 00146, Rome, Italy

    Maria Teresa Nuzzo, Marco Fiocchetti, Pierangela Totta, Antonella Cardinale & Maria Marino

  2. Department of Medical, Surgical, Neurological, Metabolic, and Ageing Sciences, University of Campania Luigi Vanvitelli, Naples, Italy

    Mariarosa A. B. Melone

  3. Institute of Biosciences and Bioresources (IBBR-CNR), Naples, Italy

    Mariarosa A. B. Melone, Paolo Ascenzi & Maria Marino

  4. S. Lucia Foundation Hospital IRCCS, Laboratory of Neuroanatomy, Rome, Italy

    Antonella Cardinale & Francesca R. Fusco

  5. Area of Neuroscience, International School for Advanced Studies (SISSA), Trieste, Italy

    Stefano Gustincich

  6. Department of Neuroscience and Brain Technologies, Italian Institute of Technologies (IIT), Genoa, Italy

    Stefano Gustincich

  7. Department of Health Science, University of Eastern Piedmont, Novara, Italy

    Francesca Persichetti

  8. Interdepartmental Laboratory for Electron Microscopy, Roma Tre University, Via della Vasca Navale 79, 00146, Rome, Italy

    Paolo Ascenzi

Authors
  1. Maria Teresa Nuzzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marco Fiocchetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pierangela Totta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mariarosa A. B. Melone
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Antonella Cardinale
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Francesca R. Fusco
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stefano Gustincich
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Francesca Persichetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Paolo Ascenzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Maria Marino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maria Marino.

Ethics declarations

All experiments were approved by the Animal Ethics Committee of S. Lucia Foundation and were conducted in accordance with Italian legislation and European regulations (Guideline 86/609/EEC).

ᅟ

Conflict of Interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Supplementary Figure 1.

Western blot analyses of NGB and HTT levels in (A) SK-N-BE and (B) MCF-7 cells stimulated for 24 h with either vehicle or E2 (10−9 M). The amount of protein was normalized by comparison with vinculin levels. The data are typical Western blots of three independent experiments. (C) Confocal microscopy analysis (original magnification × 63) of NGB (red) and HTT (green) co-immuno-localization in MCF-7 cells treated with either vehicle or E2 (10–9 M) for 24 h. Yellow signals indicates NGB-HTT co-staining in a single Z-stack plane. Representative images from three different experiments are shown in up panel. The 8.2 IMARIS software was used to quantify NGB-HTT merged signals. Data are the mean ± SD of three different experiments. p < 0.001 was calculated with Student’s t test versus vehicle-treated samples (*). Scale bars =5 μm. (GIF 41 kb)

High Resolution Image (TIFF 1527 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nuzzo, M.T., Fiocchetti, M., Totta, P. et al. Huntingtin polyQ Mutation Impairs the 17β-Estradiol/Neuroglobin Pathway Devoted to Neuron Survival. Mol Neurobiol 54, 6634–6646 (2017). https://doi.org/10.1007/s12035-016-0337-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-016-0337-x

Keywords

Search

Navigation