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Molecular clues to pathogenesis in prion diseases
M. Laurent and G. Johannin
Service d' Imagerie Cellulaire, Universite Paris-Sud, Orsay Cedex, France
Offprint requests to: Dr. Michel Laurent, Service d'imagerie Cellulaire,
URA 116 CNRS. Bat 440, Universite Paris-Sud, 91405 Orsay Cedex,
France
Summary. The infectious agent of the transmissible
spongiform encephalopathies (TSE) resembles a virus in
that it propagates in vivo and has distinct strains.
However, compelling evidence strongly suggests that a
posttranslational structural alteration in a glycoprotein
PrPC (the normal, cellular isoform of the so-called prion
protein) is responsible for pathogenesis of these diseases.
According to this hypothesis - now close to being
generally accepted -, iatrogen, sporadic and familial
forms of TSE would have the same molecular
mechanism: the conversion of PrPC into a protease resistant isoform PrPSc kinetically behaves as an
autocatalytic process which, combined with the high
turnover rate of the normal isoform, may endow the
system with bistability properties and subsequent
threshold behavior between normal and pathogenic
steady - states. Normal prion protein seems to be
necessary for long- term survival of Purkinje
neurons, regulation of circadian rhythms and, more
controversially, for normal synaptic function. At least
part of the pathology might be due to the unavailability
of normal isoform rather than to the accumulation of
PrPSc. NMR structure of the normal mouse prion protein
reveals a short, unexpected /3-sheet which might be a
nucleation site for the conformational transition between
PrPC and PrPSc. Prion diseases may challenge the edged
distinction that we use to make between informational
(DNA) and functional (proteins) macromolecules .
Pathogenic mechanism of prions might also be involved
in other proteins to achieve and pass on their
conformation. Hence, structural inheritance at the
molecular level might be the missing link for
the understanding of the structural inheritance
processes featured at the cellular level. Moreover,
evolutionary paradigm postulating a primitive RNA
world is weakened by the mechanism of prion
diseases. Histol Histopathol 12, 583-594
(1997)
Key words: Prion diseases, Prion protein, Spongiform
encephalopathies, Bistability, Structural inheritance
DOI: 10.14670/HH-12.583
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