Lysosomes as key organelles in the pathogenesis of prion encephalopathies

L. László, J. Lowe, T. Self, N. Kenward, M. Landon, T. McBride, C. Farquhar, I. McConnell, J. Brown, J. Hope, R. J. Mayer

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Abstract

The causation, structural origin, and mechanism of formation of spongiform lesions in transmissible encephalopathies are unknown. We have used immunogold electron microscopy to locate ubiquitin conjugates, hsp 70, and β-glucuronidase (markers of the lysosomal compartment) and prion protein (PrP) in both control and scrapie-infected mouse brain. In scrapie-infected brain, lysosomes and lysosome-related structures (multivesicular and tubulovesicular dense bodies) are present in abnormally high numbers in neuronal cell processes. These structures contain PrP, together with the lysosomal markers ubiquitin conjugates, hsp 70, and β-glucuronidase, which could also be identified spilling from tubulovesicular dense bodies into areas of early rarefaction in neuronal processes; we suggest that these areas of rarefaction are the precursor lesions of spongiform change. We advance the hypothesis that spongiform change is brought about by cytoskeletal disruption in neuronal processes caused by liberation of hydrolytic enzymes from lysosomes overloaded with the abnormal isoform of PrP (PrP(sc)). We suggest that the lysosomal system is probably acting as the bioreactor for processing of normal PrP to the abnormal isoform. The continuous production of increasing quantities of abnormal PrP(sc) in lysosome-related bodies will eventually cause disruption of the lysosomal membrane with destruction of the neuronal cytoskeleton and the initiation of vacuolation. Later, death of the cell will be associated with release of the PrP(sc) isoform into the extracellular environment. Repeated rounds of phagocytosis, lysosomal biogenesis of PrP(sc), lysosomal membrane rupture, hydrolytic enzyme release, and neuronal lysis will lead to an exponential increase in cell damage and cell death. The recognition of the central role played by lysosomes in the pathogenesis of this group of diseases opens new avenues for potential therapeutic intervention.

Original languageEnglish
Pages (from-to)333-341
Number of pages9
JournalJournal of Pathology
Volume166
Issue number4
Publication statusPublished - 1992

Fingerprint

Prions
Brain Diseases
Lysosomes
Organelles
Scrapie
Protein Isoforms
Glucuronidase
Ubiquitin
Cell Death
Membranes
Prion Proteins
Brain
Bioreactors
Enzymes
Cytoskeleton
Phagocytosis
Causality
Rupture
Electron Microscopy

Keywords

  • Dementia
  • Heat-shock proteins
  • Lysosome
  • Prion protein
  • Scrapie
  • Spongiform change
  • Ubiquitin

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

László, L., Lowe, J., Self, T., Kenward, N., Landon, M., McBride, T., ... Mayer, R. J. (1992). Lysosomes as key organelles in the pathogenesis of prion encephalopathies. Journal of Pathology, 166(4), 333-341.

Lysosomes as key organelles in the pathogenesis of prion encephalopathies. / László, L.; Lowe, J.; Self, T.; Kenward, N.; Landon, M.; McBride, T.; Farquhar, C.; McConnell, I.; Brown, J.; Hope, J.; Mayer, R. J.

In: Journal of Pathology, Vol. 166, No. 4, 1992, p. 333-341.

Research output: Contribution to journalArticle

László, L, Lowe, J, Self, T, Kenward, N, Landon, M, McBride, T, Farquhar, C, McConnell, I, Brown, J, Hope, J & Mayer, RJ 1992, 'Lysosomes as key organelles in the pathogenesis of prion encephalopathies', Journal of Pathology, vol. 166, no. 4, pp. 333-341.
László L, Lowe J, Self T, Kenward N, Landon M, McBride T et al. Lysosomes as key organelles in the pathogenesis of prion encephalopathies. Journal of Pathology. 1992;166(4):333-341.
László, L. ; Lowe, J. ; Self, T. ; Kenward, N. ; Landon, M. ; McBride, T. ; Farquhar, C. ; McConnell, I. ; Brown, J. ; Hope, J. ; Mayer, R. J. / Lysosomes as key organelles in the pathogenesis of prion encephalopathies. In: Journal of Pathology. 1992 ; Vol. 166, No. 4. pp. 333-341.
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