Skip to main content
SpringerLink
Log in

Proteolysis and myelin breakdown: a review of recent histochemical and biochemical studies

  • Review
  • Published:
The Histochemical Journal Aims and scope Submit manuscript

Synopsis

Proteins are important constituents of the myelin sheath and serve to maintain its structural integrity. One of the protein components is susceptible to tryptic digestion and may be regarded as a particularly vulnerable part of the myelin sheath. The initial events in myelin breakdown may involve disruption of lipid-protein attachments followed later by chemical degradation of released lipids.

In Wallerian degeneration the activity of proteolytic enzymes increases by 12 hr after nerve section. Proteolytic enzyme activity increases in the prodromal phase of diphtheritic neuropathy. Extracts of degenerating nerve cause proteolysis of normal myelin with loss of trypanophilic basic protein and lipid; selective loss of basic protein occurs very early in Wallerian degeneration and has also been found in and around plaques of multiple sclerosis. Proteolytic activity is increased at the edges of ‘active’ multiple sclerosis lesions. It has been shown that the basic encephalitogenic protein is susceptible to digestion by neural proteases, yielding an active encephalitogenic fragment.

It is inferred from these collective observations that proteases play an important role in early myelin breakdown and may also be implicated in the pathogenesis of multiple sclerosis plaques by digesting basic protein, by releasing lipid from its attachment to such protein, and by liberating an active encephalitogenic peptide. The factors responsible for the activation and release of proteases remain unknown.

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

Similar content being viewed by others

References

  • Abercrombie, M. &Johnson, M. L. (1946). Quantitative histology of Wallerian degeneration, I.J. Anat. (Lond.) 80, 37–50.

    Google Scholar 

  • Adams, C. W. M. (1957). Ap-dimethylaminobenzaldehyde-nitrite methanol for the histochemical demonstration of tryptophan and related compounds.J. clin. Path. 10, 56–62.

    Google Scholar 

  • Adams, C. W. M. (1958). The application of histochemical methods for protein identification in the study of certain pathological problems.Proc. Roy. Soc. Med. 51, 339–43.

    Google Scholar 

  • Adams, C. W. M. (1962). The histochemistry of the myelin sheath. InNeurochemistry, pp. 85–112 (ed. K. A. C. Elliott, I. H. Page and J. H. Quastel). Springfield, Ill.: C. C. Thomas.

    Google Scholar 

  • Adams, C. W. M. (1968). The histochemistry of proteolytic enzymes and lipoproteins in the normal and diseased nervous system. InMacromolecules and the Function of the Neuron, pp. 111–20 (ed. Z. Lodin and S. P. R. Rose). Amsterdam: Excerpta Medica Foundation.

    Google Scholar 

  • Adams, C. W. M., Abdulla, Y. H., Turner, D. R. &Bayliss, O. B. (1968). Subcellular preparation of peripheral nerve myelin.Nature, Lond.,220, 171–3.

    Google Scholar 

  • Adams, C. W. M. &Bayliss, O. B. (1961). Histochemistry of myelin. III. Peripheral nerve cathepsin.J. Histochem. Cytochem. 9, 473–6.

    Google Scholar 

  • Adams, C. W. M. &Bayliss, O. B. (1968). Histochemistry of myelin. V. Trypsindigestible and trypsin-resistant proteins.J. Histochem. Cytochem. 16, 110–14.

    Google Scholar 

  • Adams, C. W. M. &Davison, A. N. (1965). The myelin sheath. InNeurohistochemistry, pp. 332–400 (ed. C. W. M. Adams), Amsterdam: Elsevier.

    Google Scholar 

  • Adams, C. W. M., Davison, A. N. &Gregson, N. A. (1963). Enzyme inactivity of myelin: histochemical and biochemical evidence.J. Neurochem. 10, 383–95.

    Google Scholar 

  • Adams, C. W. M. &Glenner, G. C. (1962). Histochemistry of myelin. IV. Aminopeptidase activity in CNS and PNS.J. Neurochem. 9, 233–9.

    Google Scholar 

  • Adams, C. W. M. & Hallpike, J. F. (1968). Lipid-protein relationships in normal and degenerating myelin. InProc. Internat. Symp. Biochemistry and Histochemistry of Myelin and Demyelination, Poznan, 1968, in press.

  • Adams, C. W. M. &Leibowitz, S. (1969). The general pathology of demyelinating disease. InStructure and Function of Nervous Tissue, Vol. III (ed. G. H. Bourne). New York: Academic Press, in press.

    Google Scholar 

  • Adams, C. W. M. &Tuqan, N. A. (1961a). The histochemical demonstration of protease by a gelatin-silver film substrate.J. Histochem. Cytochem. 9, 469–72.

    Google Scholar 

  • Adams, C. W. M. &Tuqan, N. A. (1961b). Histochemistry of myelin. II. Proteins, lipid-protein dissociation and proteinase activity in Wallerian degeneration.J. Neurochem. 6, 334–41.

    Google Scholar 

  • Ansell, G. B. &Richter, D. (1954). Evidence for a ‘neutral proteinase’ in brain tissue.Biochim. biophys. Acta 13, 92–7.

    Google Scholar 

  • Benetato, G., Gabrielescu, E. &Boros, I. (1965). The histochemistry of cerebral proteases in experimental allergic encephalomyelitis.Rev. Rouman. Physiol. 2, 379–84.

    Google Scholar 

  • Bubis, J. J. &Wolman, M. (1965). Hydrolytic enzymes in Wallerian degeneration.Israel J. med. Sci.,1, 410–14.

    Google Scholar 

  • Chao, L. P. &Einstein, E. R. (1968). Isolation and characterization of an active fragment from enzymatic degradation of encephalitogenic protein.J. biol. Chem. 243, 6050–5.

    Google Scholar 

  • Coleman, R. &Finean, J. B. (1966). Preparation and properties of isolated plasma membrane from guinea-pig tissues.Biochem. biophys. Acta 125, 197–206.

    Google Scholar 

  • De Duve, C. &Wattiaux, R. (1966). Functions of lysosomes.Ann. Rev. Physiol. 28, 435–492.

    Google Scholar 

  • De Duve, C., Wattiaux, R. &Bandhuin, P. (1962). Distribution of enzymes between subcellular fractions in animal tissues.Adv. Enzymol. 24, 291–358.

    Google Scholar 

  • Dickerson, J. W. T. (1968) The composition of nervous tissues. InApplied Neurochemistry, pp. 48–118 (ed. A. N. Davison and J. Dobbing). Oxford: Blackwell.

    Google Scholar 

  • Edlbacher, S., Goldschmidt, E. &Schläppi, V. (1934). Uber die enzyme des gehirns.Hoppe-Seyler's Z. physiol. Chem. 227, 118–23.

    Google Scholar 

  • Engström, H. &Wersäll, J. (1958). Myelin sheath structure in nerve fibre demyelinization and branching regions.Expl Cell Res. 14, 414–25.

    Google Scholar 

  • Fernández-Moran, H. &Finean, J. B. (1957). Electron microscope and low-angle X-ray diffraction studies of the nerve myelin sheath.J. biophys. biochem. Cytol. 3, 725–48.

    Google Scholar 

  • Field, E. J. &Raine, C. S. (1966). Experimental allergic encephalomyelitis (an electron microscopic study).Am. J. Path. 49, 537–53.

    Google Scholar 

  • Finean, J. B. (1954). X-ray analysis of the structure of peripheral nerve myelin.Nature, Lond.,173, 549–50.

    Google Scholar 

  • Folch, J. &Lees, M. (1951). Proteolipids, a new type of tissue lipoprotein.J. biol. Chem. 191, 807–17.

    Google Scholar 

  • Friede, R. L. (1961). Enzyme histochemical studies in multiple sclerosis.Arch. Neurol. (Chic.) 5, 433–43.

    Google Scholar 

  • Gent, W. L. G., Gregson, N. A., Gammack, D. B. &Roper, J. H. (1964). The lipid-protein unit in myelin.Nature, Lond.,204, 553–5.

    Google Scholar 

  • Glimsted, G. &Wohlfart, G. (1960–61). Electron microscopic observations on Wallerian degeneration in peripheral nerves.Acta morph. neerl.-scand. 3, 135–46.

    Google Scholar 

  • Gould, R. P. & Holt, S. J. (1961). Observations on acid phosphatase and esterases in the rat sciatic nerve undergoing Wallerian degeneration.Proc. Anat. Soc. Gt. Britain & N. Ireland, 45–8.

  • Guroff, G. (1964). A neutral, calcium-activated proteinase from the soluble fraction of rat brain.J. biol. Chem. 239, 149–55.

    Google Scholar 

  • Hallpike, J. F. & Adams, C. W. M. (1968). Proteolytic enzymes in myelin breakdown. InProc. Internat. Symp. Biochemistry and Histochemistry of Myelin and Demyelination. Poznan, 1968, in press.

  • Hallpike, J. F., Adams, C. W. M. & Bayliss, O. B. (1969a). Histochemistry of myelin. VIII. Protelytic activity around multiple sclerosis plaques.Histochem. J. ms. submitted for publication.

  • Hallpike, J. F., Adams, C. W. M. & Bayliss, O. B. (1969b). Histochemistry of myelin. IX. Neutral and acid proteinases in early Wallerian degeneration.Histochem. J. ms. submitted for publication.

  • Hallpike, J. F., Adams, C. W. M. & Bayliss, O. B. (1969c). Histochemistry of myelin. X. Proteolysis of normal myelin and release of lipid by extracts of degenerating nerve.Histochem. J. ms. submitted for publication.

  • Hallpike, J. F., Adams, C. W. M. & Bayliss, O. B. (1969d). Histochemistry of myelin. XI. Loss of basic protein in early myelin breakdown and multiple sclerosis plaques.Histochem. J. ms. submitted for publication.

  • Holtzman, E. &Novikoff, A. B. (1965). Lysosomes in the rat sciatic nerve following crush.J. Cell Biol. 27, 651–69.

    Google Scholar 

  • Ibrahim, M. Z. M. &Adams, C. W. M. (1963). The relationship between enzyme activity and neuroglia in plaques of multiple sclerosis.J. Neurol. Neurosurg. Psychiat. 26, 101–10.

    Google Scholar 

  • Jacobs, J. M., Cavanagh, J. B. &Mellick, R. S. (1966). Intraneural injection of diphtheria toxin.Br. J. exp. Path. 47, 507–17.

    Google Scholar 

  • Kerekes, M. F., Feszt, T. &Kovacs, A. (1965). Catheptic activity in the cerebral tissue of the rabbit during allergic encephalomyelitis.Experientia 21, 42–3.

    Google Scholar 

  • Kies, M. W., Murphy, J. B. &Alvord, E. C. (1961). Studies on the encephalitogenic factor in guinea pig CNS. InChemical Pathology of the Nervous System, pp. 147–206 (ed. J. Folch-Pi). Oxford: Pergamon Press.

    Google Scholar 

  • Kies, M. W. &Schwimmer, S. (1942). Observations on proteinase in brain.J. biol. Chem. 145, 685–91.

    Google Scholar 

  • Krebs, H. A. (1931). Über die proteolyse der tumoren.Biochem. Z. 238, 174–96.

    Google Scholar 

  • Lampert, P. W. (1965). Demyelination and remyelination in experimental allergic encephalomyelitis, further electron microscopic observations.J. Neuropath. exp. Neurol. 24, 371–85.

    Google Scholar 

  • Lampert, P. W. &Schochet, S. S. (1968). Demyelination and remyelination in lead neuropathy.J. Neuropath. exp. Neurol. 27, 527–45.

    Google Scholar 

  • Lumsden, C. E., Robertson, D. M. &Blight, R. (1966). Chemical studies on experimental allergic encephalomyelitis. Peptide as the common denominator in all encephalitogenic antigens.J. Neurochem. 13, 127–62.

    Google Scholar 

  • Marks, N. &Lajtha, A. (1963). Protein breakdown in the brain: subcellular distribution and properties of neutral and acid proteinases.Biochem. J. 89, 438–47.

    Google Scholar 

  • Marks, N. &Lajtha, A. (1965). Separation of acid and neutral proteinases of brain.Biochem. J. 97, 74–83.

    Google Scholar 

  • McDonald, W. I. (1967). Structural and functional changes in human and experimental neuropathy. InModern Trends in Neurology, Vol. 4, pp. 145–64 (ed. Denis Williams). London: Butterworths.

    Google Scholar 

  • Nakao, A., Davis, W. J. &Einstein, E. R. (1966a). Basic proteins from the acidic extracts of bovine spinal cord. I. Isolation and characterization.Biochim. biophys. Acta 130, 163–70.

    Google Scholar 

  • Nakao, A., Davis, W. J. &Einstein, E. R. (1966b). Basic proteins from the acidic extracts of bovine spinal cord. II. Encephalitogenic, immunologic and structural interrelationships.Biochim. biophys. Acta 130, 171–9.

    Google Scholar 

  • Nathaniel, E. J. H. &Pease, D. C. (1963). Degenerative changes in rat dorsal roots during Wallerian degeneration.J. Ultrastruct. Res. 9, 511–32.

    Google Scholar 

  • O'Brien, J. S. (1965). Stability of the myelin membrane.Science 147, 1099–1107.

    Google Scholar 

  • Peters, A. (1960). Formation and structure of myelin sheaths in the CNS.J. biophys. biochem. Cytol. 8, 431–46.

    Google Scholar 

  • Porcellati, G. &Curti, B. (1960). Proteinase activity of peripheral nerves during Wallerian degeneration.J. Neurochem. 5, 277–82.

    Google Scholar 

  • Porcellati, G. &Thompson, R. H. S. (1957). The effect of nerve section on the free amino acids of nervous tissue.J. Neurochem. 1, 340–7.

    Google Scholar 

  • Rinne, U. K. &Riekkinen, P. J. (1968). Esterase, peptidase and proteinase activity of human cerebrospinal fluid in multiple sclerosis.Acta neurol. Scand. 44, 156–67.

    Google Scholar 

  • Rossiter, R. J. (1955). Biochemistry of demyelination. InNeurochemistry, 1st Ed., p. 696–714 (ed. K. A. C. Elliott, I. H. Page and J. H. Quastel). Springfield, Ill: C. C. Thomas.

    Google Scholar 

  • Schmidt, W. J. (1936). Doppelbrechung und Feinbau der Markscheide der Nervenfasern.Z. Zellforsch. 23, 657–76.

    Google Scholar 

  • Schmitt, F. O. (1950). The ultrastructure of the nerve myelin sheath.Res. Publ. Ass. nerv. ment. Dis. 28, 255–67.

    Google Scholar 

  • Tuqan, N. A. &Adams, C. W. M. (1961). Histochemistry of myelin. I. Proteins and lipid-protein complexes in the normal sheath.J. Neurochem. 6, 327–33.

    Google Scholar 

  • Vandenheuvel, F. A. (1964). Study of biological structure at the molecular level with stereo model projections. II. The structure of myelin in relation to other membrane systems.J. Am. Oil Chem. Soc. 42, 481–92.

    Google Scholar 

  • Webster, H. De F. (1962). Transient, focal accumulation of axonal mitochondria during the early stages of Wallerian degeneration.J. Cell Biol. 12, 361–77.

    Google Scholar 

  • Webster, H. De F., Spiro, D., Waksman, B. &Adams, R. D. (1961). Phase and electron microscopic studies of experimental demyelination. II: Schwann cell changes in guinea pig sciatic nerves during experimental diphtheritic neuritis.J. Neuropath. exp. Neurol. 20, 5–34.

    Google Scholar 

  • Weller, R. O. (1965). Diphtheritic neuropathy in the chicken: an electron-microscopic study.J. Path. Bact. 89, 591–8.

    Google Scholar 

  • Weller, R. O., &Mellick, R. S. (1966). Acid phosphatase and lysosome activity in diphtheritic neuropathy and Wallerian degeneration.Br. J. exp. Path. 47, 425–34.

    Google Scholar 

  • Wolfgram, F. &Rose, A. S. (1961). A study of some component proteins of central and peripheral nerve myelin.J. Neurochem. 8, 161–8.

    Google Scholar 

  • Wolman, M. &Hestrin-Lerner, S. (1960). A histochemical contribution to the study of molecular morphology of the myelin sheath.J. Neurochem. 5, 114–20.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, Guy's Hospital Medical School, London, UK

    J. F. Hallpike & C. W. M. Adams

Authors
  1. J. F. Hallpike
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. W. M. Adams
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Research Associate supported by the Multiple Sclerosis Society.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hallpike, J.F., Adams, C.W.M. Proteolysis and myelin breakdown: a review of recent histochemical and biochemical studies. Histochem J 1, 559–578 (1969). https://doi.org/10.1007/BF01012862

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01012862

Keywords

Search

Navigation