Journal of Endocrinological Investigation

, Volume 37, Issue 8, pp 729–737 | Cite as

Altered expression of 3-betahydroxysterol delta-24-reductase/selective Alzheimer’s disease indicator-1 gene in Huntington’s disease models

  • Athina Samara
  • Mariarita Galbiati
  • Paola Luciani
  • Cristiana Deledda
  • Elio Messi
  • Alessandro Peri
  • Roberto Maggi
Original Article

Abstract

Introduction

3-betahydroxysterol delta-24-reductase (DHCR24), also called selective Alzheimer’s disease indicator-1, is a crucial enzyme in cholesterol biosynthesis with neuroprotective properties that is downregulated in brain areas affected by Alzheimer’s disease.

Aim

In the present study, we investigated modifications of DHCR24 expression in models of Huntington’s disease (HD), a neurodegenerative disorder caused by a polyglutamine expansion in huntingtin (Htt) protein that induces degeneration of cerebral cortex and striatum as well as lateral hypothalamic abnormality.

Methods

Basal expression of DHCR24 and its modulation after oxidative stress were evaluated in rat striatal precursors cells (ST14A) transfected with wild-type (Htt) or mutant Htt (mHtt) and in brain tissue of an HD mouse model (R6/2).

Results

The results showed that DHCR24 transcript levels were decreased in ST14A cells expressing mHtt and in the brain of symptomatic R6/2 mice, but were significantly increased in ST14A cells overexpressing wild-type Htt. In addition, we demonstrated that, in the striatal precursors, the decrease of DHCR24 expression in response to oxidative stress was modified according to the presence of Htt or of its mutant form. Preliminary results indicated a modification of DHCR24 expression in post-mortem brain samples of HD patients.

Conclusions

In conclusion, these results support the hypothesis of a possible role of DHCR24 in HD.

Keywords

DHCR24 Neurodegeneration Cholesterol Oxidative stress Huntingtin Seladin-1 

Abbreviations

DHCR24

3-betahydroxysterol delta-24-reductase

HD

Huntington’s disease

AD

Alzheimer’s disease

Htt

Huntingtin

mHtt

Mutant Htt

18S

Ribosomal 18S subunit

Notes

Acknowledgments

This study was supported by Ministero Istruzione Università e Ricerca (MIUR) (R.M., A.P.), Ente Cassa di Risparmio di Firenze and from Regione Toscana “Bando Salute 2009″, Telethon Foundation (R.M., M.G.). The authors thank Dr.Richard Quinton (Newcastle, UK) and Dr. Francesca Fusco (Rome) for the support in critical reading of the manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Waterham H, Koster J, Romeijn G et al (2001) Mutations in the 3beta-hydroxysterol Delta24-reductase gene cause desmosterolosis, an autosomal recessive disorder of cholesterol biosynthesis. Am J Hum Genet 69:685–694PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Porter FD (2003) Human malformation syndromes due to inborn errors of cholesterol synthesis. Curr Opin Pediatr 15:607–613PubMedCrossRefGoogle Scholar
  3. 3.
    Greeve I, Hermans-Borgmeyer I, Brellinger C et al (2000) The human DIMINUTO/DWARF1 homolog seladin-1 confers resistance to Alzheimer’s disease-associated neurodegeneration and oxidative stress. J Neurosci 20:7345–7352PubMedGoogle Scholar
  4. 4.
    Crameri A, Biondi E, Kuehnle K et al (2006) The role of seladin-1/DHCR24 in cholesterol biosynthesis, APP processing and Abeta generation in vivo. EMBO J 25:432–443PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Cecchi C, Rosati F, Pensalfini A et al (2008) Seladin-1/DHCR24 protects neuroblastoma cells against Abeta toxicity by increasing membrane cholesterol content. J Cell Mol Med 12:1990–2002PubMedCrossRefGoogle Scholar
  6. 6.
    Kuehnle K, Crameri A, Kälin R et al (2008) Prosurvival effect of DHCR24/Seladin-1 in acute and chronic responses to oxidative stress. Mol Cell Biol 28:539–550PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Peri A, Serio M (2008) Neuroprotective effects of the Alzheimer’s disease-related gene seladin-1. J Mol Endocrinol 41:251–261PubMedCrossRefGoogle Scholar
  8. 8.
    Lu X, Kambe F, Cao X et al (2008) 3beta-Hydroxysteroid-delta24 reductase is a hydrogen peroxide scavenger, protecting cells from oxidative stress-induced apoptosis. Endocrinology 149:3267–3273PubMedCrossRefGoogle Scholar
  9. 9.
    Peri A, Benvenuti S, Luciani P, Deledda C, Cellai I (2011) Membrane cholesterol as a mediator of the neuroprotective effects of estrogens. Neuroscience 191:107–117PubMedCrossRefGoogle Scholar
  10. 10.
    Numakawa T, Matsumoto T, Numakawa Y, Richards M, Yamawaki S, Kunugi H (2011) Protective action of neurotrophic factors and estrogen against oxidative stress-mediated neurodegeneration. J Toxicol 2011:405194PubMedCentralPubMedGoogle Scholar
  11. 11.
    Sharpe LJ, Wong J, Garner B, Halliday GM, Brown AJ (2012) Is seladin-1 really a selective Alzheimer’s disease indicator? J Alzheimers Dis 30:35–39PubMedGoogle Scholar
  12. 12.
    The Huntington Disease Collaborative Research (1993) G. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983CrossRefGoogle Scholar
  13. 13.
    Rigamonti D, Bauer JH, De-Fraja C et al (2000) Wild-type huntingtin protects from apoptosis upstream of caspase-3. J Neurosci 20:3705–3713PubMedGoogle Scholar
  14. 14.
    Rigamonti D, Sipione S, Goffredo D, Zuccato C, Fossale E, Cattaneo E (2001) Huntingtin’s neuroprotective activity occurs via inhibition of procaspase-9 processing. J Biol Chem 276:14545–14548PubMedCrossRefGoogle Scholar
  15. 15.
    Zuccato C, Valenza M, Cattaneo E (2010) Molecular mechanisms and potential therapeutical targets in Huntington’s disease. Physiol Rev 90:905–981PubMedCrossRefGoogle Scholar
  16. 16.
    Saleh N, Moutereau S, Durr A et al (2009) Neuroendocrine disturbances in Huntington’s disease. PLoS One 4:e4962PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Petersén A, Björkqvist M (2006) Hypothalamic-endocrine aspects in Huntington’s disease. Eur J Neurosci 24:961–967PubMedCrossRefGoogle Scholar
  18. 18.
    Browne SE, Beal MF (2006) Oxidative damage in Huntington’s disease pathogenesis. Antioxid Redox Signal 8:2061–2073PubMedCrossRefGoogle Scholar
  19. 19.
    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. Trends Neurosci 24:182–188PubMedCrossRefGoogle Scholar
  20. 20.
    Sipione S, Rigamonti D, Valenza M et al (2002) Early transcriptional profiles in huntingtin-inducible striatal cells by microarray analyses. Hum Mol Genet 11:1953–1965PubMedCrossRefGoogle Scholar
  21. 21.
    Valenza M, Leoni V, Tarditi A et al (2007) Progressive dysfunction of the cholesterol biosynthesis pathway in the R6/2 mouse model of Huntington’s disease. Neurobiol Dis 28:133–142PubMedCrossRefGoogle Scholar
  22. 22.
    Valenza M, Leoni V, Karasinska JM et al (2010) Cholesterol defect is marked across multiple rodent models of Huntington’s disease and is manifest in astrocytes. J Neurosci 30:10844–10850PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Leoni V, Mariotti C, Nanetti L et al (2011) Whole body cholesterol metabolism is impaired in Huntington’s disease. Neurosci Lett 494:245–249PubMedCrossRefGoogle Scholar
  24. 24.
    Valenza M, Rigamonti D, Goffredo D et al (2005) Dysfunction of the cholesterol biosynthetic pathway in Huntington’s disease. J Neurosci 25:9932–9939PubMedCrossRefGoogle Scholar
  25. 25.
    Leoni V, Mariotti C, Tabrizi SJ et al (2008) Plasma 24S-hydroxycholesterol and caudate MRI in pre-manifest and early Huntington’s disease. Brain 131:2851–2859PubMedCrossRefGoogle Scholar
  26. 26.
    Ermak G, Hench KJ, Chang KT, Sachdev S, Davies KJ (2009) Regulator of calcineurin (RCAN1-1L) is deficient in Huntington disease and protective against mutant huntingtin toxicity in vitro. J Biol Chem 284:11845–11853PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Mangiarini L, Sathasivam K, Seller M et al (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87:493–506PubMedCrossRefGoogle Scholar
  28. 28.
    Rigamonti D, Bolognini D, Mutti C et al (2007) Loss of huntingtin function complemented by small molecules acting as repressor element 1/neuron restrictive silencer element silencer modulators. J Biol Chem 282:24554–24562PubMedCrossRefGoogle Scholar
  29. 29.
    Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:e45PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    DiFiglia M, Sapp E, Chase KO et al (1997) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277:1990–1993PubMedCrossRefGoogle Scholar
  31. 31.
    Carter RJ, Lione LA, Humby T et al (1999) Characterization of progressive motor deficits in mice transgenic for the human Huntington’s disease mutation. J Neurosci 19:3248–3257PubMedGoogle Scholar
  32. 32.
    Quinti L, Chopra V, Rotili D, et al. (2010) Evaluation of histone deacetylases as drug targets in Huntington’s disease models. Study of HDACs in brain tissues from R6/2 and CAG140 knock-in HD mouse models and human patients and in a neuronal HD cell model. PLoS Curr 2. doi: 10.1371/currents.RRN1172
  33. 33.
    Bowles KR, Brooks SP, Dunnett SB, Jones L (2012) Gene expression and behaviour in mouse models of HD. Brain Res Bull 88:276–284PubMedCrossRefGoogle Scholar
  34. 34.
    Vonsattel JP, Keller C (2008) Del Pilar Amaya M. Neuropathology of Huntington’s disease. Handb Clin Neurol 89:599–618PubMedCrossRefGoogle Scholar
  35. 35.
    Kuhn A, Goldstein DR, Hodges A et al (2007) Mutant huntingtin’s effects on striatal gene expression in mice recapitulate changes observed in human Huntington’s disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage. Hum Mol Genet 16:1845–1861PubMedCrossRefGoogle Scholar
  36. 36.
    Sarchielli E, Marini M, Ambrosini S, et al. (2014) Multifaceted roles of BDNF and FGF2 in human striatal primordium development. An in vitro study. Exp Neurol 257C:130–147Google Scholar
  37. 37.
    Katsuno M, Adachi H, Sobue G (2009) Getting a handle on Huntington’s disease: the case for cholesterol. Nat Med 15:253–254PubMedCrossRefGoogle Scholar
  38. 38.
    Wu C, Miloslavskaya I, Demontis S, Maestro R, Galaktionov K (2004) Regulation of cellular response to oncogenic and oxidative stress by Seladin-1. Nature 432:640–645PubMedCrossRefGoogle Scholar
  39. 39.
    McGrath K, Li X, Puranik R et al (2009) Role of 3beta-hydroxysteroid-delta 24 reductase in mediating antiinflammatory effects of high-density lipoproteins in endothelial cells. Arterioscler Thromb Vasc Biol 29:877–882PubMedCrossRefGoogle Scholar
  40. 40.
    Otis M, Battista M, Provencher M et al (2008) From integrative signalling to metabolic disorders. J Steroid Biochem Mol Biol 109:224–229PubMedCrossRefGoogle Scholar
  41. 41.
    Sarkar D, Imai T, Kambe F et al (2001) The human homolog of Diminuto/Dwarf1 gene (hDiminuto): a novel ACTH-responsive gene overexpressed in benign cortisol-producing adrenocortical adenomas. J Clin Endocrinol Metab 86:5130–5137PubMedCrossRefGoogle Scholar
  42. 42.
    Chae JI, Kim DW, Lee N et al (2012) Quantitative proteomic analysis of induced pluripotent stem cells derived from a human Huntington’s disease patient. Biochem J 446:359–371PubMedCrossRefGoogle Scholar
  43. 43.
    Illuzzi JL, Vickers CA, Kmiec EB (2011) Modifications of p53 and the DNA damage response in cells expressing mutant form of the protein huntingtin. J Mol Neurosci 45:256–268PubMedCrossRefGoogle Scholar
  44. 44.
    Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP (1985) Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 44:559–577PubMedCrossRefGoogle Scholar
  45. 45.
    Jenkins BG, Koroshetz WJ, Beal MF, Rosen BR (1993) Evidence for impairment of energy metabolism in vivo in Huntington’s disease using localized 1H NMR spectroscopy. Neurology 43:2689–2695PubMedCrossRefGoogle Scholar
  46. 46.
    Rajkowska G, Selemon LD, Goldman-Rakic PS (1998) Neuronal and glial somal size in the prefrontal cortex: a postmortem morphometric study of schizophrenia and Huntington disease. Arch Gen Psychiatry 55:215–224PubMedCrossRefGoogle Scholar
  47. 47.
    Nieweg K, Schaller H, Pfrieger FW (2009) Marked differences in cholesterol synthesis between neurons and glial cells from postnatal rats. J Neurochem 109:125–134PubMedCrossRefGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2014

Authors and Affiliations

  • Athina Samara
    • 1
    • 3
  • Mariarita Galbiati
    • 1
  • Paola Luciani
    • 2
  • Cristiana Deledda
    • 2
  • Elio Messi
    • 1
  • Alessandro Peri
    • 2
  • Roberto Maggi
    • 1
  1. 1.Department of Pharmacological and Biomolecular Sciences, Section of Biomedicine and Endocrinology, and Centre of Excellence on Neurodegenerative Diseases (CEND)Università degli Studi di MilanoMilanItaly
  2. 2.Endocrine Unit, Department of Clinical Physiopathology, Center for Research, Transfer and High Education on Chronic, Inflammatory, Degenerative and Neoplastic Disorders for the Development of Novel Therapies’ (DENOThe)University of FlorenceFlorenceItaly
  3. 3.University of Oslo and Norwegian Center for Stem Cell ResearchOsloNorway

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