Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Neurology
Published in: Journal of Neurology 8/2014

01-08-2014 | Review

Myelin damage due to local quantitative abnormalities in normal prion levels: evidence from subacute combined degeneration and multiple sclerosis

Authors: Giuseppe Scalabrino, Daniela Veber

Published in: Journal of Neurology | Issue 8/2014

Login to get access

Abstract

Cobalamin (Cbl) deficiency causes an imbalance in some cytokines and growth factors in the central nervous system and peripheral nervous system (PNS) of the rat, and in the serum and cerebrospinal fluid (CSF) of adult Cbl-deficient (Cbl-D) patients. It is conceivable that this imbalance triggers subsequent cellular events. We hypothesized that an imbalance in normal prion (PrPC) levels and/or synthesis might be involved in the pathogenesis of Cbl-D neuropathy, and demonstrated that: (1) Cbl deficiency induces excess PrPC in rat spinal cord (SC) and PNS, concomitantly with myelin damage and PNS electrophysiological abnormalities; (2) the SC increase is mediated by a local Cbl deficiency-induced excess of tumor necrosis factor-α; (3) myelinotrophic Cbl and epidermal growth factor upregulate PrPC-mRNA levels in rat SC; (4) treatment with anti-PrPC octapeptide repeat region antibodies normalizes the ultrastructure of the Cbl-D rat SC and PNS myelins, and the PNS electrophysiological abnormalities, without modifying their Cbl-D status; (5) PrPC administration to otherwise normal rats causes SC and PNS myelin lesions and PNS electrophysiological abnormalities, similar to those of Cbl-D neuropathy; (6) CSF and serum PrPC concentrations in Cbl-D patients are significantly higher than in controls; and (7) these concentrations significantly correlate with their CSF and serum Cbl concentrations. CSF PrPC concentrations are significantly lower in patients with multiple sclerosis (MS) than neurological controls, but serum PrPC concentrations in patients with non-Cbl-D anemias and CSF PrPC concentrations in patients with non-myelin-damaging neurological diseases are normal.
Literature
1.
Scalabrino G (2001) Subacute combined degeneration one century later. The neurotrophic action of cobalamin (vitamin B12) revisited. J Neuropathol Exp Neurol 60:109–120PubMed
2.
Scalabrino G (2009) The multi-faceted basis of vitamin B12 (cobalamin) neurotrophism in adult central nervous system: lessons learned from its deficiency. Prog Neurobiol 88:203–220CrossRefPubMed
3.
Scalabrino G, Veber D, Mutti E (2008) Experimental and clinical evidence of the role of cytokines and growth factors in the pathogenesis of acquired cobalamin-deficient leukoneuropathy. Brain Res Rev 59:42–54CrossRefPubMed
4.
Scalabrino G, Peracchi M (2006) New insights into the pathophysiology of cobalamin deficiency. Trends Mol Med 12:247–254CrossRefPubMed
5.
6.
Scalabrino G, Nicolini G, Buccellato FR et al (1999) Epidermal growth factor as a local mediator of the neurotrophic action of vitamin B12 (cobalamin) in the rat central nervous system. FASEB J 13:2083–2090PubMed
7.
Barres BA (2008) The mystery and magic of glia: a perspective on their roles in health and disease. Neuron 60:430–440CrossRefPubMed
8.
Seifert G, Schilling K, Steinhäuser C (2006) Astrocyte dysfunction in neurological disorders: a molecular perspective. Nat Rev Neurosci 7:194–206CrossRefPubMed
9.
De Keyser J, Mostert JP, Koch MW (2008) Dysfunctional astrocytes as key players in the pathogenesis of central nervous system disorders. J Neurol Sci 267:3–16CrossRefPubMed
10.
11.
12.
Liedtke W, Edelmann W, Bieri PL et al (1996) GFAP is necessary for the integrity of CNS white matter architecture and long-term maintenance of myelination. Neuron 17:607–615CrossRefPubMed
13.
Solomon LR (2007) Disorders of cobalamin (vitamin B12) metabolism: emerging concepts in pathophysiology, diagnosis and treatment. Blood Rev 21:113–130CrossRefPubMed
14.
15.
Hathout L, El-Saden S (2011) Nitrous oxide-induced B12 deficiency myelopathy: perspectives on the clinical biochemistry of vitamin B12. J Neurol Sci 301:1–8CrossRefPubMed
16.
Green R, Jacobsen DW, Van Tonder SV et al (1982) Absorption of biliary cobalamin in baboons following total gastrectomy. J Lab Clin Med 100:771–777PubMed
17.
Scalabrino G (2005) Cobalamin (vitamin B12) in subacute combined degeneration and beyond: traditional interpretations and novel theories. Exp Neurol 192:463–479CrossRefPubMed
18.
Scalabrino G (2009) Vitamin-regulated cytokines and growth factors in the CNS and elsewhere. J Neurochem 111:1309–1326CrossRefPubMed
19.
Kaput J, Rodriguez RL (2004) Nutritional genomics: the next frontier in the postgenomic era. Physiol Genom 16:166–177CrossRef
20.
Burdge GC, Lillycrop KA (2010) Nutrition, epigenetics, and developmental plasticity: implications for understanding human disease. Annu Rev Nutr 30:315–339CrossRefPubMed
21.
Stover PJ, Caudill MA (2008) Genetic and epigenetic contributions to human nutrition and health: managing genome-diet interactions. J Am Diet Assoc 108:1480–1487CrossRefPubMed
22.
Chawla RK, Watson WH, Eastin CE et al (1998) S-adenosylmethionine deficiency and TNF-α in lypopolysaccharide-induced hepatic injury. Am J Physiol 275:G125–G129PubMed
23.
Watson WH, Zhao Y, Chawla RK (1999) S-Adenosylmethionine attenuates the lipopolysaccharide-induced expression of gene for tumor necrosis factor α. Biochem J 342:21–25PubMedCentralCrossRefPubMed
24.
McClain CJ, Hill DB, Song Z et al (2002) S-Adenosylmethionine, cytokines, and alcoholic liver disease. Alcohol 27:185–192CrossRefPubMed
25.
Veal N, Hsieh C-L, Xiong S et al (2004) Inhibition of lipopolysaccharide-stimulated TNF-α promoter activity by S-adenosylmethionine and 5′-methylthioadenosine. Am J Physiol 287:G352–G362
26.
Song Z, Uriarte S, Sahoo R et al (2005) S-adenosylmethionine (SAMe) modulates interleukin-10 and interleukin-6, but not TNF, production via the adenosine (A2) receptor. Biochim Biophys Acta 1743:205–213CrossRefPubMed
27.
Veber D, Mutti E, Galmozzi E et al (2006) Increased levels of the CD40:CD40 ligand dyad in the cerebrospinal fluid of rats with vitamin B12(cobalamin)-deficient central neuropathy. J Neuroimmunol 176:24–33CrossRefPubMed
28.
Aguzzi A, Baumann F, Bremer J (2008) The prion’s elusive reason for being. Annu Rev Neurosci 31:439–477CrossRefPubMed
29.
Linden R, Martins VR, Prado MA et al (2008) Physiology of the prion protein. Physiol Rev 88:673–728CrossRefPubMed
30.
Nishida N, Tremblay P, Sugimoto T et al (1999) A mouse prion protein transgene rescues mice deficient for the prion protein gene from Purkinje cell degeneration and demyelination. Lab Invest 79:689–697PubMed
31.
Bremer J, Baumann F, Tiberi C et al (2010) Axonal prion protein is required for peripheral myelin maintenance. Nat Neurosci 13:310–318CrossRefPubMed
32.
Nazor KE, Seward T, Telling GC (2007) Motor behavioral and neuropathological deficits in mice deficient for normal prion protein expression. Biochim Biophys Acta 1772:645–653PubMedCentralCrossRefPubMed
33.
Westaway D, DeArmond SJ, Cayetano-Canlas J et al (1994) Degeneration of skeletal muscle, peripheral nerves, and the central nervous system in transgenic mice overexpressing wild-type prion proteins. Cell 76:117–129CrossRefPubMed
34.
Radovanovic I, Braun N, Giger OT et al (2005) Truncated prion protein and Doppel are myelinotoxic in the absence of oligodendrocytic PrPC. J Neurosci 25:4879–4888CrossRefPubMed
35.
Li A, Christensen HM, Stewart LR et al (2007) Neonatal lethality in transgenic mice expressing prion protein with a deletion of residues 105–125. EMBO J 26:548–558PubMedCentralCrossRefPubMed
36.
37.
38.
Mitteregger G, Vosko M, Krebs B et al (2007) The role of the octarepeat region in neuroprotective function of the cellular prion protein. Brain Pathol 17:174–183PubMedCentralCrossRefPubMed
39.
Li A, Piccardo P, Barmada SJ et al (2007) Prion protein with an octapeptide insertion has impaired neuroprotective activity in transgenic mice. EMBO J 26:2777–2785PubMedCentralCrossRefPubMed
40.
Flechsig E, Shmerling D, Hegyi I et al (2000) Prion protein devoid of the octapeptide repeat region restores susceptibility to scrapie in PrP knockout mice. Neuron 27:399–408CrossRefPubMed
41.
Chiesa R, Piccardo P, Ghetti B, Harris DA (1998) Neurological illness in transgenic mice expressing a prion protein with an insertional mutation. Neuron 21:1339–1351CrossRefPubMed
42.
Chiesa R, Drisaldi B, Quaglio E et al (2000) Accumulation of protease-resistant prion protein (PrP) and apoptosis of cerebellar granule cells in transgenic mice expressing a PrP insertional mutation. Proc Natl Acad Sci USA 97:5574–5579PubMedCentralCrossRefPubMed
43.
44.
Mead S, Webb TE, Campbell TA et al (2007) Inherited prion disease with 5-OPRI: phenotype modification by repeat length and codon 129. Neurology 69:730–738CrossRefPubMed
45.
Kaski DN, Pennington C, Beck J et al (2011) Inherited prion disease with 4-octapeptide repeat insertion: disease requires the interaction of multiple genetic risk factors. Brain 134:1829–1838CrossRefPubMed
46.
Solomon IH, Schepker JA, Harris DA (2010) Prion neurotoxicity: insights from prion protein mutants. Curr Issues Mol Biol 12:51–61PubMed
47.
Martins VR, Beraldo FH, Hajj GN et al (2010) Prion protein: orchestrating neurotrophic activities. Curr Issues Mol Biol 12:63–86PubMed
48.
Wadsworth JD, Asante EA, Collinge J (2010) Contribution of transgenic models to understanding human prion disease. Neuropathol Appl Neurobiol 36:576–597PubMedCentralCrossRefPubMed
49.
Chiesa R, Harris DA (2001) Prion diseases: what is the neurotoxic molecule? Neurobiol Dis 8:743–763CrossRefPubMed
50.
Veber D, Mutti E, Tacchini L et al (2008) Indirect down-regulation of nuclear NF-κB levels by cobalamin in the spinal cord and liver of the rat. J Neurosci Res 86:1380–1387CrossRefPubMed
51.
Moser M, Colello RJ, Pott U, Oesch B (1995) Developmental expression of the prion protein gene in glial cells. Neuron 14:509–517CrossRefPubMed
52.
Follet J, Lemaire-Vieille C, Blanquet-Grossard F et al (2002) PrP expression and replication by Schwann cells: implications in prion spreading. J Virol 76:2434–2439PubMedCentralCrossRefPubMed
53.
Sauer H, Wefer K, Vetrugno V et al (2003) Regulation of intrinsic prion protein by growth factors and TNF-α: the role of intracellular reactive oxygen species. Free Radic Biol Med 35:586–594CrossRefPubMed
54.
Kuwahara C, Kubosaki A, Nishimura T et al (2000) Enhanced expression of cellular prion protein gene by insulin or nerve growth factor in immortalized mouse neuronal precursor cell lines. Biochem Biophys Res Commun 268:763–766CrossRefPubMed
55.
Williams AE, van Dam A-M, Man-A-Hing WKH et al (1994) Cytokines, prostaglandins and lipocortin-1 are present in the brains of scrapie-infected mice. Brain Res 654:200–206CrossRefPubMed
56.
Campbell IL, Eddleston M, Kemper P et al (1994) Activation of cerebral cytokine gene expression and its correlation with onset of reactive astrocyte and acute-phase response gene expression in scrapie. J Virol 68:2383–2387PubMedCentralPubMed
57.
58.
59.
Glatzel M, Stoeck K, Seeger H et al (2005) Human prion diseases. Molecular and clinical aspects. Arch Neurol 62:545–552CrossRefPubMed
60.
Scalabrino G, Veber D, Mutti E et al (2012) Cobalamin (vitamin B12) regulation of PrPC, PrPC-mRNA and copper levels in rat central nervous system. Exp Neurol 233:380–390CrossRefPubMed
61.
Scalabrino G, Mutti E, Veber D et al (2011) The octapeptide repeat PrPC region and cobalamin-deficient polyneuropathy of the rat. Muscle Nerve 44:957–967CrossRefPubMed
62.
Oltean S, Banerjee R (2003) Nutritional modulation of gene expression and homocysteine utilization by vitamin B12. J Biol Chem 278:20778–20784CrossRefPubMed
63.
Marguerite V, Beri-Dexheimer M, Ortiou S et al (2007) Cobalamin potentiates vinblastine cytotoxicity through downregulation of mdr-1 gene expression in HepG2 cells. Cell Physiol Biochem 20:967–976CrossRefPubMed
64.
Nahvi A, Barrick JE, Breaker RR (2004) Coenzyme B12 riboswitches are widespread genetic control elements in prokaryotes. Nucleic Acids Res 32:143–150PubMedCentralCrossRefPubMed
65.
66.
Miller A, Korem M, Almog R, Galboiz Y (2005) Vitamin B12, demyelination, remyelination and repair in multiple sclerosis. J Neurol Sci 233:93–97CrossRefPubMed
67.
68.
Scalabrino G, Galimberti D, Mutti E et al (2010) Loss of epidermal growth factor regulation by cobalamin in multiple sclerosis. Brain Res 1333:64–71CrossRefPubMed
69.
70.
Imitola J, Chitnis T, Khoury SJ (2005) Cytokines in multiple sclerosis: from bench to bedside. Pharmacol Ther 106:163–177CrossRefPubMed
71.
Baranzini SE, Elfstrom C, Chang SY et al (2000) Transcriptional analysis of multiple sclerosis brain lesions reveals a complex pattern of cytokine expression. J Immunol 165:6576–6582CrossRefPubMed
72.
Loeb JA (2007) Neuroprotection and repair by neurotrophic and gliotrophic factors in multiple sclerosis. Neurology 68(Suppl 3):S38–S42CrossRefPubMed
73.
Scalabrino G, Veber D, Briani C et al (2013) Cobalamin as a regulator of serum and cerebrospinal fluid levels of normal prions. J Clin Neurosci 20:134–138CrossRefPubMed
74.
Roucou X, Gains M, LeBlanc AC (2004) Neuroprotective functions of prion protein. J Neurosci Res 75:153–161CrossRefPubMed
75.
Steinacker P, Hawlik A, Lehnert S et al (2010) Neuroprotective function of cellular prion protein in a mouse model of amyotrophic lateral sclerosis. Am J Pathol 176:1409–1420PubMedCentralCrossRefPubMed
76.
Dupuis L, Mbebi C, Gonzalez de Aguilar JL et al (2002) Loss of prion protein in a transgenic model of amyotrophic lateral sclerosis. Mol Cell Neurosci 19:216–224CrossRefPubMed
77.
Robberecht W, Philips T (2013) The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci 14:248–264CrossRefPubMed
78.
79.
80.
81.
Colby DW, Prusiner SB (2011) Prions. Cold Spring Harb Perspect. Biol 3:a006833
82.
83.
84.
85.
Kang SH, Li Y, Fukaya M et al (2013) Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nat Neurosci 16:571–579PubMedCentralCrossRefPubMed
86.
87.
Meyne F, Gloeckner S, Ciesielczyk B et al (2009) Total prion protein levels in the cerebrospinal fluid are reduced in patients with various neurological disorders. J Alzheimers Dis 17:863–873PubMed
88.
Benarroch EE (2009) Oligodendrocytes. Susceptibility to injury and involvement in neurologic disease. Neurology 72:1779–1785CrossRefPubMed
89.
Barnett MH, Prineas JW (2004) Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 55:458–468CrossRefPubMed
90.
Okada K, Tanaka H, Temporin K et al (2010) Methylcobalamin increases Erk1/2 and Akt activities through the methylation cycle and promotes nerve regeneration in a rat sciatic nerve injury model. Exp Neurol 222:191–203CrossRefPubMed
91.
92.
Buccellato FR, Foi L, Veber D et al (2004) Different uptake of cobalamin (vitamin B12) by astrocytes and oligodendrocytes isolated from rat spinal cord. Glia 45:406–411CrossRefPubMed
93.
Knapp PE, Adams MH (2004) Epidermal growth factor promotes oligodendrocyte process formation and regrowth after injury. Exp Cell Res 296:135–144CrossRefPubMed
94.
95.
Yamada M, Ikeuchi T, Hatanaka H (1997) The neurotrophic action and signalling of epidermal growth factor. Prog Neurobiol 51:19–37CrossRefPubMed
96.
Moore CS, Abdullah SL, Brown A et al (2011) How factors secreted from astrocytes impact myelin repair. J Neurosci Res 89:13–21CrossRefPubMed
97.
Metadata
Title
Myelin damage due to local quantitative abnormalities in normal prion levels: evidence from subacute combined degeneration and multiple sclerosis
Authors
Giuseppe Scalabrino
Daniela Veber
Publication date
01-08-2014
Publisher
Springer Berlin Heidelberg
Published in
Journal of Neurology / Issue 8/2014
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI
https://doi.org/10.1007/s00415-013-7152-3

Other articles of this Issue 8/2014

Journal of Neurology 8/2014 Go to the issue

Journal club

Narcolepsy: environment, genes and treatment

Original Communication

Prolonged survival in adult neurofibromatosis type I patients with recurrent high-grade gliomas treated with bevacizumab

Original Communication

Stroke in sports: a case series

Original Communication

How predictors and patterns of stroke recurrence after a TIA differ during the first year of follow-up

Original Communication

Multiple sclerosis fatigue relief by bilateral somatosensory cortex neuromodulation

Pioneers in Neurology

Robert Bartholow (1831–1904)