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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1114 ADRIANO AGUZZI AND ANNA MARIA CALELLA<br />
ber of investigators still contend that scrapie is caused by<br />
a viruslike particle containing a scrapie-specific nucleic<br />
acid that encodes the information expressed by each<br />
isolate (78). But to date, no such polynucleotide has been<br />
identified, despite the use of a wide variety of techniques,<br />
including the measurement of nucleic acids in purified<br />
preparations. An alternative hypothesis is that PrP Sc alone<br />
is capable of transmitting the disease <strong>and</strong> that the characteristics<br />
of PrP Sc are modified by a cellular nucleic acid<br />
(512). This accessory cellular polynucleotide is postulated<br />
to induce its own synthesis upon transmission from one<br />
host to another, but there is currently no experimental<br />
evidence to support its existence.<br />
In striking contrast, mice expressing Prnp transgenes<br />
have demonstrated that the level of PrP expression is<br />
inversely related to the incubation time (412). Taken together,<br />
these observations indicate that PrP Sc itself is the<br />
molecule in which prion “strain”-specific information is<br />
encrypted. Preliminary immunochemical evidence suggests<br />
that PrP Sc of different strains expose different<br />
epitopes (438) <strong>and</strong> display different degrees of stability to<br />
chaotropic salts (390). Infrared spectroscopy measurements<br />
have shown that types of PrP Sc associated with<br />
distinct hamster TSE strains can possess different conformations,<br />
even though they are derived from PrP with<br />
the same amino acid sequence (101). This could be interpreted<br />
as indirect evidence for conformational differences<br />
or could indicate that different PrP Sc strains associate<br />
with different molecules of proteinaceous or other<br />
nature.<br />
Both PrP C <strong>and</strong> PrP Sc exist in three main glycosylation<br />
states: unglycosylated, monoglycosylated, <strong>and</strong> diglycosylated.<br />
The relative ratios of these three forms of PrP Sc<br />
differ in various prion strains. In some cases, such differences<br />
are remarkably robust <strong>and</strong> are widely used for<br />
prion strain typing. On the basis of the fragment size <strong>and</strong><br />
the relative abundance of individual b<strong>and</strong>s identified by<br />
gel electrophoresis, three distinct patterns of PrP Sc (types<br />
1–3) have been identified for sporadic <strong>and</strong> iatrogenic CJD<br />
cases (118, 381). In contrast, all cases of vCJD display a<br />
novel pattern, designated type 4 by Collinge <strong>and</strong> type III<br />
by Parchi <strong>and</strong> Gambetti (Fig. 4). Interestingly, brain extracts<br />
from BSE-infected cattle as well as BSE-inoculated<br />
macaques exhibited a type 4 pattern. Even more intriguing,<br />
transmission of BSE or vCJD to mice produced<br />
mouse PrP Sc with a type 4 pattern indistinguishable from<br />
the original inoculum (219). These findings strongly support<br />
the hypothesis that vCJD is the result of BSE transmission<br />
to humans.<br />
It is clear that in some patients suffering from CJD,<br />
multiple distinct types of CJD-associated PrP Sc molecules<br />
coexist within the same patient (396). However,<br />
the molecular basis for these differences in glycosylation<br />
is poorly understood, <strong>and</strong> the mechanisms by<br />
which differences in PrP Sc glycosylation states affect<br />
Physiol Rev VOL 89 OCTOBER 2009 www.prv.org<br />
FIG. 4. Representation of the three glycosylated PrP Sc moieties<br />
(un-, mono-, <strong>and</strong> diglycosylated PrP Sc ) in immunoblots of brain extracts<br />
after digestion with proteinase K. Different inocula result in specific<br />
mobilities of the three PrP b<strong>and</strong>s as well as different predominance of<br />
certain b<strong>and</strong>s (top panel). These characteristic patterns can be retained,<br />
or changed to other predictable patterns after passage in wild-type mice<br />
(bottom panel). On the basis of the fragment size <strong>and</strong> the relative<br />
abundance of individual b<strong>and</strong>s, three distinct patterns (PrP Sc types 1–3)<br />
were defined for sCJD <strong>and</strong> iCJD cases. In contrast, all cases of vCJD <strong>and</strong><br />
of BSE displayed a novel pattern, designated as type 4 pattern.<br />
the disease remain unanswered. It has been proposed<br />
that the relative prevalence of distinct glycoforms may<br />
determine the structure of infectious PrP seeds <strong>and</strong><br />
thereby determine strain properties (116), although little<br />
physical evidence for this assertion existed until recently.<br />
This hypothesis is certainly compatible with the report<br />
that strains differ in their ability to infect hosts with<br />
restricted PrP glycosylation, <strong>and</strong> certain strains may only<br />
produce disease in hosts whose PrP C harbors specific<br />
carbohydrate side chains (501).<br />
G. Prion-like Properties of Additional<br />
Misfolded <strong>Protein</strong>s<br />
The “seeded nucleation” theory (238) described for<br />
PrP may also apply to amyloid formation in other protein<br />
misfolding disorders (PMDs). In fact, protein conformational<br />
changes associated with the pathogenesis of most<br />
PMDs result in the formation of abnormal proteins that<br />
are rich in -sheet structure, partially resistant to proteolysis,<br />
<strong>and</strong> have a high tendency to form larger-order<br />
aggregates, similar to PrP Sc . Amyloid formation depends<br />
on the slow interaction of misfolded protein monomers to<br />
form oligomeric nuclei, around which a faster phase of<br />
elongation takes place. The ability of oligomeric species<br />
to seed their own growth is analogous to the self-propagating<br />
activity of prions.<br />
These theoretical considerations are supported by<br />
extensive experimental data (474). In addition, it has been