Home Normal prions as a new target of cobalamin (vitamin B12) in rat central nervous system
Article
Licensed
Unlicensed Requires Authentication

Normal prions as a new target of cobalamin (vitamin B12) in rat central nervous system

  • Giuseppe Scalabrino EMAIL logo and Daniela Veber
Published/Copyright: November 21, 2012
Become an author with De Gruyter Brill
Submit Manuscript Author Information
Clinical Chemistry and Laboratory Medicine
From the journal Clinical Chemistry and Laboratory Medicine Volume 51 Issue 3

Abstract

The pathogenesis of cobalamin (Cbl)-deficient (Cbl-D) neuropathy and the role of normal prions (PrPcs) in myelin maintenance are both subjects of debate. We have demonstrated that Cbl deficiency damages myelin by increasing tumor necrosis factor (TNF)-α, and decreasing epidermal growth factor (EGF) levels in the rat central nervous system (CNS). It is known that TNF-α and EGF regulate PrPc expression in vitro, and that myelin vacuolation, reactive astrocytosis and microglial activation are common to rat Cbl-D neuropathy and some prion diseases. We have shown that Cbl deficiency leads to high levels of PrPcs [particularly the octapeptide repeat (OR) domains] in the rat CNS thereby damaging the spinal cord (SC) myelin, and that chronic intra-cerebroventricular treatment with anti-OR antibodies normalizes SC myelin morphology. We have also found that PrPc levels are increased in the SC of Cbl-D rats by the time the myelin lesions appear, and that this increase is mediated by excess myelinotoxic TNF-α and prevented by EGF treatment, which has proved to be as effective as Cbl in preventing Cbl deficiency-induced lesions. Cbl stimulates PrPc mRNA-related synthesis in Cbl-D SC and duodenum, two rat tissues that are severely affected by Cbl deficiency. New PrPc synthesis is a common effect of various myelinotrophic agents, two of which (EGF and anti-TNF-α antibodies) also stimulate PrPc mRNA-related synthesis in the SC of Cbl-D rats.

Keywords: cerebrospinal fluid; cobalamin deficiency; epidermal growth factor; normal prion protein; spinal cord; tumor necrosis factor-α
Corresponding author: Giuseppe Scalabrino, Laboratory of Neuropathology, ‘Città Studi’ Department, University of Milan, via Mangiagalli 31, 20133 Milan, Italy, Phone: +39 02 50315348, Fax: +39 02 50315338

We gratefully acknowledge the editorial assistance of Dr. T. Cerchiaro, Laboratory of Neuropathology, ‘Città Studi’ Department, University of Milan, Milan, Italy.

Conflict of interest statement

Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

References

1. Pant SH, Asbury AK, Richardson EP. The myelopathy of pernicious anemia: a neuropathological reappraisal. Acta Neurol Scand 1968;44(Suppl 35):1–36.Search in Google Scholar

2. Andrès E, Loukili NH, Noel E, Kaltenbach G, Abdelgheni MB, Perrin AE, et al. Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ 2004;171:251–9.10.1503/cmaj.1031155Search in Google Scholar PubMed PubMed Central

3. Lindenbaum J, Healton EB, Savage DG, Brust JC, Garrett TJ, Podell ER, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1988;318:1720–8.10.1056/NEJM198806303182604Search in Google Scholar PubMed

4. Carmel R. Pernicious anemia. The expected findings of very low serum cobalamin levels, anemia, and macrocytosis are often lacking. Arch Int Med 1988;148:1712–4.10.1001/archinte.1988.00380080016007Search in Google Scholar

5. Scalabrino G, Veber D, Mutti E. Experimental and clinical evidence of the role of cytokines and growth factors in the pathogenesis of acquired cobalamin-deficient leukoneuropathy. Brain Res Rev 2008;59:42–54.10.1016/j.brainresrev.2008.05.001Search in Google Scholar PubMed

6. Scalabrino G. The multi-faceted basis of vitamin B12 (cobalamin) neurotrophism in adult central nervous system: lessons learned from its deficiency. Prog Neurobiol 2009;88:203–20.10.1016/j.pneurobio.2009.04.004Search in Google Scholar PubMed

7. Nishida N, Tremblay P, Sugimoto T, Shigematsu K, Shirabe S, Petromilli C, et al. A mouse prion protein transgene rescues mice deficient for the prion protein gene from Purkinje cell degeneration and demyelination. Lab Invest 1999;79:689–97.Search in Google Scholar

8. Sakaguchi S. Molecular biology of prion protein and its first homologous protein. J Med Invest 2007;54:211–23.10.2152/jmi.54.211Search in Google Scholar PubMed

9. Solomon IH, Schepker JA, Harris DA. Prion neurotoxicity: insights from prion protein mutants. Curr Issues Mol Biol 2010;12:51–61.10.21775/9781912530076.01Search in Google Scholar

10. Baumann F, Tolnay M, Brabeck C, Pahnke J, Kloz U, Niemann HH, et al. Lethal recessive myelin toxicity of prion protein lacking its central domain. EMBO J 2007;26:538–47.10.1038/sj.emboj.7601510Search in Google Scholar PubMed PubMed Central

11. Linden R, Martins VR, Prado MA, Cammarota M, Izquierdo I, Brentani RR. Physiology of the prion protein. Physiol Rev 2008;88:673–728.10.1152/physrev.00007.2007Search in Google Scholar PubMed

12. Aguzzi A, Baumann F, Bremer J. The prion’s elusive reason for being. Annu Rev Neurosci 2008;31:439–77.10.1146/annurev.neuro.31.060407.125620Search in Google Scholar PubMed

13. Radovanovic I, Braun N, Giger OT, Mertz K, Miele G, Prinz M, et al. Truncated prion protein and Doppel are myelinotoxic in the absence of oligodendrocytic PrPc. J Neurosci 2005;25:4879–88.10.1523/JNEUROSCI.0328-05.2005Search in Google Scholar

14. Kovacs GG, Budka H. Prion diseases: from protein to cell pathology. Am J Pathol 2008;172:555–65.10.2353/ajpath.2008.070442Search in Google Scholar

15. Wadsworth JD, Collinge J. Molecular pathology of human prion disease. Acta Neuropathol 2011;121:69–77.10.1007/s00401-010-0735-5Search in Google Scholar

16. Kuwahara C, Kubosaki A, Nishimura T, Nasu Y, Nakamura Y, Saeki K, et al. Enhanced expression of cellular prion protein gene by insulin or nerve growth factor in immortalized mouse neuronal precursor cell lines. Biochem Biophys Res Commun 2000;268:763–6.10.1006/bbrc.2000.2152Search in Google Scholar

17. Zawlik I, Witusik M, Hulas-Bigoszewska K, Piaskowski S, Szybka M, Golanska, et al. Regulation of PrPc expression: nerve growth factor (NGF) activates the prion gene promoter through the MEK1 pathway in PC12 cells. Neurosci Lett 2006;400:58–62.10.1016/j.neulet.2006.02.021Search in Google Scholar

18. Sauer H, Wefer K, Vetrugno V, Pocchiari M, Gissel C, Sachinidis A, et al. Regulation of intrinsic prion protein by growth factors and TNF-α: the role of intracellular reactive oxygen species. Free Radic Biol Med 2003;35:586–94.10.1016/S0891-5849(03)00360-5Search in Google Scholar

19. Kim JI, Ju WK, Choi JH, Choi E, Carp RI, Wisniewski HM, et al. Expression of cytokine genes and increased nuclear factor-kappa B activity in the brains of scrapie-infected mice. Mol Brain Res 1999;73:17–27.10.1016/S0169-328X(99)00229-6Search in Google Scholar

20. Julius C, Heikenwalder M, Schwarz P, Marcel A, Karin M, Prinz M, et al. Prion propagation in mice lacking central nervous system NF-kappaB signalling. J Gen Virol 2008;89:1545–50.10.1099/vir.0.83622-0Search in Google Scholar

21. Campbell IL, Eddleston M, Kemper P, Oldstone MB, Hobbs MV. Activation of cerebral cytokine gene expression and its correlation with onset of reactive astrocyte and acute-phase response gene expression in scrapie. J Virol 1994;68:2383–7.10.1128/jvi.68.4.2383-2387.1994Search in Google Scholar

22. Williams AE, van Dam A-M, Man-A-Hing WK, Berkenbosch F, Eikelenboom P, Fraser H. Cytokines, prostaglandins and lipocortin-1 are present in the brains of scrapie-infected mice. Brain Res 1994;654:200–6.10.1016/0006-8993(94)90480-4Search in Google Scholar

23. Scalabrino G, Veber D, Mutti E, Calligaro A, Milani S, Tredici G. Cobalamin (vitamin B12) regulation of PrPc, PrPc-mRNA and copper levels in rat central nervous system. Exp Neurol 2012;233:380–90.10.1016/j.expneurol.2011.11.003Search in Google Scholar

24. Mitteregger G, Vosko M, Krebs B, Xiang W, Kohlmannsperger V, Nölting S, et al. The role of the octarepeat region in neuroprotective function of the cellular prion protein. Brain Pathol 2007;17:174–83.10.1111/j.1750-3639.2007.00061.xSearch in Google Scholar

25. Li A, Piccardo P, Barmada SJ, Ghetti B, Harris DA. Prion protein with an octapeptide insertion has impaired neuroprotective activity in transgenic mice. EMBO J 2007;26:2777–85.10.1038/sj.emboj.7601726Search in Google Scholar

26. Polymenidou M, Moos R, Scott M, Sigurdson C, Shi Y-Z, Yajima B, et al. The POM monoclonals: a comprehensive set of antibodies to non-overlapping prion protein epitopes. PLoS One 2008;3:e3872.10.1371/journal.pone.0003872Search in Google Scholar

27. Kalra S, Ahuja R, Mutti E, Veber D, Seetharam S, Scalabrino G, et al. Cobalamin-mediated regulation of transcobalamin receptor levels in rat organs. Arch Biochem Biophys 2007;463:128–32.10.1016/j.abb.2007.03.011Search in Google Scholar

28. Buccellato FR, Miloso M, Braga M, Nicolini G, Morabito A, Pravettoni G, et al. Myelinolytic lesions in spinal cord of cobalamin-deficient rats are TNF-α-mediated. FASEB J 1999;13:297–304.10.1096/fasebj.13.2.297Search in Google Scholar

29. Scalabrino G, Tredici G, Buccellato FR, Manfridi A. Further evidence for the involvement of epidermal growth factor in the signaling pathway of vitamin B12 (cobalamin) in the rat central nervous system. J Neuropathol Exp Neurol 2000;59:808–14.10.1093/jnen/59.9.808Search in Google Scholar

30. Tsiroulnikov K, Chobert JM, Haertlé T. Copper-dependent degradation of recombinant ovine prion protein. FEBS J 2006;273:1959–65.10.1111/j.1742-4658.2006.05209.xSearch in Google Scholar

31. Owen F, Poulter M, Collinge J, Leach M, Lofthouse R, Crow TJ, et al. A dementing illness associated with a novel insertion in the prion protein gene. Mol Brain Res 1992;13:155–7.10.1016/0169-328X(92)90056-HSearch in Google Scholar

32. Krasemann S, Zerr I, Weber T, Poser S, Kretzschmar H, Hunsmann G, et al. Prion disease associated with a novel nine octapeptide repeat insertion in the PRNP gene. Mol Brain Res 1995;34:173–6.10.1016/0169-328X(95)00175-RSearch in Google Scholar

33. Mead S. Prion disease genetics. Eur J Hum Genet 2006;14:273–81.10.1038/sj.ejhg.5201544Search in Google Scholar

34. Mead S, Webb TE, Campbell TA, Beck J, Linehan JM, Rutherfoord S, et al. Inherited prion disease with 5-OPRI: phenotype modification by repeat length and codon 129. Neurology 2007;69:730–8.10.1212/01.wnl.0000267642.41594.9dSearch in Google Scholar

35. Chiesa R, Harris DA. Prion diseases: what is the neurotoxic molecule? Neurobiol Dis 2001;8:743–63.10.1006/nbdi.2001.0433Search in Google Scholar

36. Flechsig E, Shmerling D, Hegyi I, Raeber AJ, Fischer M, Cozzio A, et al. Prion protein devoid of the octapeptide repeat region restores susceptibility to scrapie in PrP knockout mice. Neuron 2000;27:399–408.10.1016/S0896-6273(00)00046-5Search in Google Scholar

37. Cohen FE, Prusiner SB. Structural studies of prion proteins. In: Prusiner SB, editor. Prion biology and diseases. New York: Cold Spring Harbor Laboratory Press, 1999:191–228.Search in Google Scholar

38. Behrens A, Aguzzi A. Small is not beautiful: antagonizing functions for the prion protein PrPc and its homologue Dpl. Trends Neurosci 2002;25:150–4.10.1016/S0166-2236(00)02089-0Search in Google Scholar

39. Prusiner SB. An introduction to prion biology and diseases. In: Prusiner SB, editor. Prion biology and diseases. New York: Cold Spring Harbor Laboratory Press, 1999:1–66.Search in Google Scholar

40. Pradines E, Loubet D, Mouillet-Richard S, Manivet P, Launay JM, Kellermann O, et al. Cellular prion protein coupling to TACE-dependent TNF-α shedding controls neurotransmitter catabolism in neuronal cells. J Neurochem 2009;110:912–23.10.1111/j.1471-4159.2009.06176.xSearch in Google Scholar PubMed

41. Oltean S, Banerjee R. Nutritional modulation of gene expression and homocysteine utilization by vitamin B12. J Biol Chem 2003;278:20778–84.10.1074/jbc.M300845200Search in Google Scholar PubMed

Received: 2012-7-23
Accepted: 2012-10-24
Published Online: 2012-11-21
Published in Print: 2013-03-01

©2013 by Walter de Gruyter Berlin Boston

Articles in the same Issue

  1. Masthead
  2. Masthead
  3. Editorial
  4. Special issue on advances and controversies in B vitamins and choline
  5. Reviews
  6. B-Vitamin dependent methionine metabolism and alcoholic liver disease
  7. Metabolic crosstalk between choline/1-carbon metabolism and energy homeostasis
  8. Proteomics of vitamin B12 processing
  9. Unexpected high plasma cobalamin/Proposal for a diagnostic strategy
  10. Clinical recognition and aspects of the cerebral folate deficiency syndromes
  11. Choline-containing phospholipids: relevance to brain functional pathways
  12. The ‘golden age’ of DNA methylation in neurodegenerative diseases
  13. Mechanisms of the beneficial effects of vitamin B6 and pyridoxal 5-phosphate on cardiac performance in ischemic heart disease
  14. The diagnostic utility of folate receptor autoantibodies in blood
  15. Red cell or serum folate: what to do in clinical practice?
  16. Formate: an essential metabolite, a biomarker, or more?
  17. The role of homocysteine in bone remodeling
  18. Mini Reviews
  19. Neuroprotective actions of perinatal choline nutrition
  20. Normal prions as a new target of cobalamin (vitamin B12) in rat central nervous system
  21. Molecular mechanisms underlying the potentially adverse effects of folate
  22. Betaine homocysteine methyltransferase (BHMT)-dependent remethylation pathway in human healthy and tumoral liver
  23. Hydrogen sulfide as an oxygen sensor
  24. Opinion Paper
  25. B vitamin therapy for homocysteine: renal function and vitamin B12 determine cardiovascular outcomes
  26. Research Articles
  27. One year B and D vitamins supplementation improves metabolic bone markers
  28. Effect of 1 year B and D vitamin supplementation on LINE-1 repetitive element methylation in older subjects
  29. Aqueous humor glycation marker and plasma homocysteine in macular degeneration
  30. Homocysteine plasma levels in patients treated with antiepileptic drugs depend on folate and vitamin B12 serum levels, but not on genetic variants of homocysteine metabolism
  31. Trends in clinical laboratory homocysteine testing from 1997 to 2010: the impact of evidence on clinical practice at a single institution
  32. Three family members with elevated plasma cobalamin, transcobalamin and soluble transcobalamin receptor (sCD320)
  33. Plasma choline and betaine correlate with serum folate, plasma S-adenosyl-methionine and S-adenosyl-homocysteine in healthy volunteers
  34. Plasma homocysteine and vitamin B12 serum levels, red blood cell folate concentrations, C677T methylenetetrahydrofolate reductase gene mutation and risk of recurrent miscarriage: a case-control study in Spain
https://doi.org/10.1515/cclm-2012-0474
Keywords for this article
cerebrospinal fluid; cobalamin deficiency; epidermal growth factor; normal prion protein; spinal cord; tumor necrosis factor-α

Articles in the same Issue

  1. Masthead
  2. Masthead
  3. Editorial
  4. Special issue on advances and controversies in B vitamins and choline
  5. Reviews
  6. B-Vitamin dependent methionine metabolism and alcoholic liver disease
  7. Metabolic crosstalk between choline/1-carbon metabolism and energy homeostasis
  8. Proteomics of vitamin B12 processing
  9. Unexpected high plasma cobalamin/Proposal for a diagnostic strategy
  10. Clinical recognition and aspects of the cerebral folate deficiency syndromes
  11. Choline-containing phospholipids: relevance to brain functional pathways
  12. The ‘golden age’ of DNA methylation in neurodegenerative diseases
  13. Mechanisms of the beneficial effects of vitamin B6 and pyridoxal 5-phosphate on cardiac performance in ischemic heart disease
  14. The diagnostic utility of folate receptor autoantibodies in blood
  15. Red cell or serum folate: what to do in clinical practice?
  16. Formate: an essential metabolite, a biomarker, or more?
  17. The role of homocysteine in bone remodeling
  18. Mini Reviews
  19. Neuroprotective actions of perinatal choline nutrition
  20. Normal prions as a new target of cobalamin (vitamin B12) in rat central nervous system
  21. Molecular mechanisms underlying the potentially adverse effects of folate
  22. Betaine homocysteine methyltransferase (BHMT)-dependent remethylation pathway in human healthy and tumoral liver
  23. Hydrogen sulfide as an oxygen sensor
  24. Opinion Paper
  25. B vitamin therapy for homocysteine: renal function and vitamin B12 determine cardiovascular outcomes
  26. Research Articles
  27. One year B and D vitamins supplementation improves metabolic bone markers
  28. Effect of 1 year B and D vitamin supplementation on LINE-1 repetitive element methylation in older subjects
  29. Aqueous humor glycation marker and plasma homocysteine in macular degeneration
  30. Homocysteine plasma levels in patients treated with antiepileptic drugs depend on folate and vitamin B12 serum levels, but not on genetic variants of homocysteine metabolism
  31. Trends in clinical laboratory homocysteine testing from 1997 to 2010: the impact of evidence on clinical practice at a single institution
  32. Three family members with elevated plasma cobalamin, transcobalamin and soluble transcobalamin receptor (sCD320)
  33. Plasma choline and betaine correlate with serum folate, plasma S-adenosyl-methionine and S-adenosyl-homocysteine in healthy volunteers
  34. Plasma homocysteine and vitamin B12 serum levels, red blood cell folate concentrations, C677T methylenetetrahydrofolate reductase gene mutation and risk of recurrent miscarriage: a case-control study in Spain
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 10.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/cclm-2012-0474/html
Scroll to top button