Rendiconti Lincei

, Volume 14, Issue 4, pp 263–279 | Cite as

Intraneuronal inclusion bodies: From Negri bodies to proteasomal dysfunction

  • Marina Bentivoglio
Article

Abstract

Rabies, a fatal viral encephalitis which infects domestic and wild animals, is an old recognized disease, but still widely distributed, especially in developing countries. The occurrence of characteristic inclusion bodies in neurons of spinal ganglia and brains of animals infected by rabies was detected by Adelchi Negri in Camillo Golgi’s laboratory and officially reported in 1903. This finding provided a breakthrough in the diagnosis of rabies. Influenced by Golgi’s studies on malaria, Negri proposed that the intracellular bodies he had observed corresponded to a parasite, which he believed to represent the pathogenetic agent of rabies. The causative agents of the disease are now known to be neurotropic RNA viruses which spread into the nervous system via retrograde axonal transport. The Negri bodies have been ascribed to accumulation of viral nucleoproteins and cellular organelles, but their nature and composition is still enigmatic, and research on the pathogenesis of rabies is hampered nowadays by lack of funding. On the other hand, interest in intraneuronal inclusions (presently considered as intracellular foci of sequestration of aggregated proteins) has recently exploded in relation to neurodegenerative diseases. In this context, failure in the clearance of proteins via the ubiquitin-proteasome pathway is raising increasing interest. This pathway involves an enzymatic cascade through which ubiquitin molecules are attached to the protein substrate, which is then degraded by the proteasome complex. Such proteolytic process, important in a variety of basic cellular functions, is the primary mechanism responsible for the elimination of damaged and misfolded proteins. Recent findings indicated that a cellular response designed to reduce the toxicity of misfolded proteins can be exploited by viruses to concentrate structural proteins at virus assembly sites. In addition, the ubiquitin-proteasome pathway was recently found to be involved in the budding process of rabies virus. Interest in the Negri bodies could thus be revived in the context of molecular and cellular studies at the forefront of neurosciences.

Key words

Rabies Viral diseases Neuroinflammation Neurodegeneration Ubiquitin-proteasome pathway 

Corpi inclusi intraneuronali: dai corpi di Negri alle alterazioni del proteasoma

Riassunto

La rabbia, un’encefalite virale fatale che infetta animali domestici e selvatici, è una malattia conosciuta fin dall’antichità e tuttora largamente diffusa, soprattutto nei paesi in via di sviluppo. Adelchi Negri ha descritto nel 1903, nel laboratorio di Camillo Golgi, dei corpi inclusi caratteristici in neuroni di gangli spinali e dell’encefalo di animali affetti da rabbia. Questi dati hanno consentito una svolta nella diagnosi della malattia. Influenzato dagli studi the Golgi aveva effettuato sulla malaria, Negri propose che le inclusioni intracellulari corrispondessero ad un parassita responsabile della malattia. Come è noto, gli agenti eziologici della rabbia sono invece RNA virus neurotropici, che is diffondono nel sistema nervoso attraverso il trasporto assonale retrogrado. I corpi di Negri sono stati ascritti all’accumulo di nucleoproteine virali ed organelli cellulari, ma la loro reale natura è tuttora sconosciuta e le ricerche sulla patogenesi della rabbia sono attualmente rese difficili dalla mancanza di fondi. D’altro canto, le inclusioni intraneuronali (ora considerate come aggregati proteici) destano attualmente grande interesse in relazione alle malattie neurodegenerative ed alle alterazioni dei meccanismi di degradazione di proteine anomale attraverso la via ubiquitina-proteasoma. Quest’ultima, che svolge un ruolo chiave in molte funzioni cellulari, coinvolge una cascata enzimatica nella quale molecole di ubiquitina si legano al substrato proteico, the viene poi degradato dal proteasoma. È stato recentemente ipotizzato che la risposta cellulare mirata a ridurre la tossicità di proteine anomale possa venire utilizzata da virus per concentrare proteine strutturali nei loro siti di assemblaggio. Inoltre, è stato recentemente descritto che la via ubiquitina-proteasoma è coinvolta nel processo di «budding» del virus della rabbia. I corpi di Negri potrebbero quindi suscitare un nuovo interesse nell’ambito di studi molecolari e cellulari che sono oggi in prima linea nelle neuroscienze.

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References

  1. Bentivoglio M., 1999.The discovery of axonal transport. Brain Res. Bull., 50: 383–384.CrossRefGoogle Scholar
  2. Berlucchi G., 2002.Emilio Veratti and the ring of the czarina. Rend. Fis. Acc. Lincei, s. 9, v. 13: 257–272.CrossRefGoogle Scholar
  3. Bertarelli E., 1904a. Sopra le vie per le quali il virus rabido arriva alle ghiandole salivari del cane. Arch. Sci. Med., 28: 179–191.Google Scholar
  4. Bertarelli E., 1904b. Ueber die Wege, auf denen das Wutvirus zu den Speicheldrüsen des Hundes gelangt. Centralbl. Bakt. Parasit. Infektionskrankh., 37: 213–221.Google Scholar
  5. Bertarelli E., Volpino G., 1903.Morphologische und biologische Beobachtungen über einen Fall von Wutkrankheit beim Menschen, mit besonderer Rücksicht auf die Gegenwart und Verteilung der Negrischen örpechen in Zentralnervensystem. Centralbl. Bakt. Parasit. Infektionkrankh., 35: 221–223.Google Scholar
  6. Brownell B., Tomlinson A.H., 1984.Virus diseases of the central nervous system. In:J.H. Adams, J.A.N. Corsellis, L.W. Duchen (eds.),Greenfield’s Neuropathology. 4th Edition, Arnold, London: 260–303.Google Scholar
  7. Charlton K.M., 1988.Rabies pathogenesis. In:J.B. Campbell, K.M. Charlton (eds.),Rabies. Kluwer, Boston: 101–150.Google Scholar
  8. Cowdry E.V., 1934.The problem of intranuclear inclusions in virus disease. Arch. Path., 18: 527–542.Google Scholar
  9. East M.L., Hofer H., Cox J.H., Wulle U., Wilk H., Pitra C., 2001.Regular exposure to rabies virus and lack of symptomatic disease in Serengeti spotted hyenas. Proc. Natl. Acad. Sci. USA, 98: 15026–15031.CrossRefGoogle Scholar
  10. Fermi C., 1950.La rabbia. Istituto Sieroterapico e Vaccinogeno «SCLAVO», Siena.Google Scholar
  11. Harty R.N., Brown M.E., McGettigan J.P., Wang G., Jayakar H.R., Huibregtse J.M., Whitt M.A., Schnell M.J., 2001.Rhabdoviruses and the cellular ubiquitin-proteasome system: a budding interaction. J. Virol., 75: 10623–10629.CrossRefGoogle Scholar
  12. Heath C.M., Windsor M., Wileman T., 2001.Aggresomes resemble sites specialized for virus assembly. J. Cell Biol., 153: 449–455.CrossRefGoogle Scholar
  13. Jackson A.C., 2002.Update on rabies. Curr. Opin. Neurol., 15: 327–331.CrossRefGoogle Scholar
  14. Keller J.N., Gee J., Ding Q., 2002.The proteasome in brain aging. Ageing Res. Rev., 1: 279–293.CrossRefGoogle Scholar
  15. Kelly R.M., Strick P.L., 2000.Rabies as a transneuronal tracer of circuits in the central nervous system. J. Neurosci. Meth., 103: 63–71.CrossRefGoogle Scholar
  16. Kopito R.R., 2000.Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol., 10: 524–530.CrossRefGoogle Scholar
  17. Kristensson K., Enerbäck L., Sourander P., 1970.Histochemical and ultrastructurla properties of the classical inclusion body in neurons infected with herpes simplex virus. Acta Pathol. Microbiol. Scand., 78: 595–604.Google Scholar
  18. Kristensson K., Dastur D.K., Manghani D.K., Tsiang H., Bentivoglio M., 1996.Rabies: interactions between neurons and viruses. A review of the history of Negri inclusion bodies. Neuropathol. Appl. Neurobiol., 22: 179–187.CrossRefGoogle Scholar
  19. Lafora G.R., Glueck B., 1911.Betrag zür Histopathologie der myoklonischen Epilepsie. Z. Gesamte Neurol. Psychiat., 6: 1–14.CrossRefGoogle Scholar
  20. Lechevalier H.A., Solotorovsky M., 1965.Three centuries of microbiology. McGraw-Hill, New York.Google Scholar
  21. Lentz T.L., Burrage T.G., Smith A.L, Crick J., Tignor G.H., 1982.Is the acetylcholine receptor a rabies virus receptor? Science, 215: 182–184.CrossRefGoogle Scholar
  22. Lewey F.H., 1913.Zur pathologischen Anatomie der Paralysis agitans. Deut. Zeitsh. Nervenkrank., 50: 50–55.Google Scholar
  23. Manghani D.K., Dastur D.K., Nanavaty A.N., Patel R., 1986.Pleomorphism of fine structure of rabies virus in human and experimental brain. J. Neurol. Sci., 75: 181–193.CrossRefGoogle Scholar
  24. Matsumoto S., 1962.Electron microscopy of nerve cells infected with street rabies virus. Virology, 17: 198–202.CrossRefGoogle Scholar
  25. Mazarakis N.D., Azzouz M., Rohll J.B., Ellard F.M., Wilkes F.J., Olsen A.L., Carter E.E., Barber R.D., Baban D.F., Kingsman S.M., Kingsman A.J., O’Malley K., Mitrophanous K.A., 2001.Rabies virus glycoprotein pseudotyping of lentiviral vectors enables retrograde axonal transport and access to the nervous system after peripheral delivery. Human Mol. Genetics, 10: 2109–2121.CrossRefGoogle Scholar
  26. Mazzarello P., 1999.The hidden structure: A scientific biography of Camillo Golgi. Oxford University Press, Oxford (originally published as:La struttura nascosta. Cisalpino, Bologna 1996. Translated from the Italian and edited by H.A. Buchtel and A. Badiani).Google Scholar
  27. Miyamoto K., Matsumoto S., 1967.Comparative studies between pathogens of street and fixed rabies infection. J. Exp. Med., 125: 447–456.CrossRefGoogle Scholar
  28. Negri A., 1903.Contributo allo studio dell’eziologia della rabbia. Boll. Soc. Med.-Chir. Pavia, 2: 88–115.Google Scholar
  29. Negri A., 1904.Sull’eziologia della rabbia. La dimostrazione del parassita specifico nell’infezione rabica degli uccelli. Boll. Soc. Med.-Chir. Pavia, 3: 22–25.Google Scholar
  30. Negri A., 1905.Sull’eziologia della rabbia. Note sulla morfologia e sul ciclo evolutivo del parassita specifico. Boll. Soc. Med.-Chir. Pavia, 4: 321–333.Google Scholar
  31. Negri A., 1909.Sulla morfologia e sul ciclo del parassita della rabbia (Neurocytes hydrophobiaeAlkins). Atti Acc. Lincei Mem. Fis., s. 5, v. 7: 469–485.Google Scholar
  32. Negri Luzzani L., 1913.Le diagnostic de la rage par la démonstration du parasite spécifique. Résultats de dix ans d’expériences. Ann. Inst. Pasteur, 27: 1039–1064.Google Scholar
  33. Rupprecht C.E., Dietzschold B., Wunner W.H., Koprowski H., 1991.Antigenic relationships of lyssaviruses. In:G.M. Baer (ed.)The natural history of rabies. CRC Press, Boca Raton: 69–100.Google Scholar
  34. Rupprecht C.E., Hanlon C.A., Hemachudha T., 2002.Rabies re-examined. Lancet Infect. Dis., 2: 327–343.CrossRefGoogle Scholar
  35. Taylor J.P., Hardy J., Fischbeck K.H., 2002.Toxic proteins in neurodegenerative disease. Science, 296: 1991–1995.CrossRefGoogle Scholar
  36. Veratti E., 1953.L’interpretazione dei corpi del Negri cinquant’anni dopo lo scoperta. Boll. Soc. Med.-Chir. Pavia, 67: 1–13.Google Scholar

Copyright information

© Springer 2003

Authors and Affiliations

  • Marina Bentivoglio
    • 1
  1. 1.Dipartimento di Scienze Morfologico-Biomediche Sezione di Anatomia e Istologia Facoltà di MedicinaUniversità degli Studi di VeronaVerona

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