Prions: Protein Aggregation and Infectious Diseases - Physiological ...
Prions: Protein Aggregation and Infectious Diseases - Physiological ...
Prions: Protein Aggregation and Infectious Diseases - Physiological ...
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1112 ADRIANO AGUZZI AND ANNA MARIA CALELLA<br />
FIG. 3. Schematic representation of the protein misfolding cyclic amplification (PMCA) reaction. PrP C is recruited into growing aggregates of<br />
PrP Sc ; hence, it undergoes conformational conversion <strong>and</strong> becomes PrP Sc . During PMCA, the growing PrP Sc species are disrupted by repeated<br />
sonication in the presence of detergents. This treatment generates an exp<strong>and</strong>ed population of converting units for the continuous recruitment of<br />
PrP C . The whole procedure is repeated several times. PrP C is shown as light gray spheres. PrP Sc is shown as trapezium. The original seed is in dark<br />
gray, <strong>and</strong> the newly formed PrP Sc is in light gray.<br />
An important part of the prion replication process is<br />
the propagation of prions through the fragmentation of<br />
existing fibrils. This mechanism has been experimentally<br />
verified for yeast prions (62, 491). There are indications<br />
that similar processes govern the growth of mammalian<br />
prions (94, 295) as well as non-prion-related amyloid<br />
fibrils (139).<br />
Analysis of yeast prions has shown that the mechanical<br />
frangibility of formed prion fibrils plays a key role in<br />
fibril growth, complexity, <strong>and</strong> diversity (492). The fragility<br />
of yeast prions varies substantially between different<br />
classes of fibrils, but is relatively homogeneous within a<br />
single class (237, 492). Yeast prion classes with an aggressive<br />
tendency to multiply in vivo have been found to be<br />
composed of amyloid fibrils with the highest propensity to<br />
fragment. It is interesting to note that in terms of their<br />
mechanical rigidity, amyloid fibrils can be very heterogeneous<br />
(272), implying a substantial potential for intrinsic<br />
variability in their breakage rates. Although prion propagation<br />
in mammalian tissues is likely to be inherently<br />
more convoluted, recent observations indicate that the<br />
propagation of mammalian prion strains may be kinetically<br />
similar to fungal prions. Indeed, shorter fibrils,<br />
which may result from breakage of frangible structures,<br />
are more infectious than longer fibrils (464), an observation<br />
consistent with the fact that a larger number of free<br />
ends in a short fibril population leads to more rapid<br />
conversion of soluble cellular prion protein into misfolded<br />
fibrillar form <strong>and</strong> eventually overwhelming cellular<br />
clearance mechanisms.<br />
In agreement with this idea, an inverse correlation<br />
was recently found between the stability of prion aggregates<br />
<strong>and</strong> incubation times in vivo (296), a finding that is<br />
closely analogous to results obtained in yeast prions<br />
(499). Furthermore, in in vitro growth assays of many<br />
amyloid fibril systems, it has been noted that agitation<br />
significantly enhances the overall conversion rate of proteins<br />
into fibrillar forms (255, 371, 467), indicating that<br />
fibril breakage is an essential factor determining the rate<br />
of amyloid formation. In living systems, the rate constants<br />
for prion replication are clearly influenced not only by the<br />
intrinsic strength of PrP Sc aggregates, but also by other<br />
cellular components. Molecular chaperones in yeast, for<br />
instance, have been identified as important players in the<br />
rate of prion replication (454).<br />
F. Prion Diversity<br />
Physiol Rev VOL 89 OCTOBER 2009 www.prv.org<br />
One of the most puzzling phenomena in prion biology<br />
is the existence of prion strains. Prion strains are defined<br />
as infectious isolates that, when transmitted to identical