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Basic Biomedical Research
_~ on Transmissible
Spongiform Encephalopathies
Research focused directly on the development of antemortem tests
for the diagnosis of transmissible spongiform encephalopathies
(TSEs) may prove fruitful, and certain promising approaches will
be discussed in the next chapter. However, the committee strongly believes
that the fastest way to develop rapid, noninvasive, early-stage diagnostic
tools for TSEs is through basic biomedical research that can fill gaps in the
fundamental knowledge of prions and their disease-causing properties.
The European experience provides evidence that applied research alone
is insufficient. The European Union has spent approximately 30 million
euros ($30.7 million) over the past 10 years in an attempt to develop satis-
factory postmortem diagnostic tests for BSE, yet the Western blot test, which
has been in use for three decades, is still the most commonly employed
method (personal communication, A. Aguzzi, University Hospital of Zurich,
July15, 20021.
The history of medicine also provides numerous examples of basic dis-
coveries that were essential precursors to the development of diagnostics.
For instance, before inexpensive and rapid diagnostics were available for
non-A, non-B hepatitis, the hepatitis C virus had to be identified and cloned.
Likewise, before an effective blood test became available for screening for
HIV, the virus first had to be identified and isolated.
Many brilliant and dedicated scientists have been working for more
than 20 years to solve the mysteries related to disease-causing priors. Col-
lectively they have made great progress, yet many fundamental questions
remain. To answer these questions, scientists must solve the structure of
60
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BASIC BIOMEDICAL RESEARCH ON TSEs
6
PrPSc and relate that structure to prion strain differences (see Box 3-11;
determine endogenous and exogenous mechanisms of prion replication (see
Box 3-21; clarify the pathways and pathogenic mechanisms used by prions
(see Box 3-31; and elucidate the physiological function of prpC (see Box 3-
41. Each of these priority areas for basic research on prions is discussed, in
turn, below.
STRUCTURAL FEATURES OF PRIONS
Current models of prion conformation and tertiary structure are nei-
ther complete nor conclusive. Defining the critical structural differences
between infectious and noninfectious forms of the prion protein could pro-
vide the basis for TSE diagnostics and elucidate the correlations between
PrP structures and strains. The committee believes that research to these
ends should be high priority for support by the National Prion Research
Program (NPRP).
Defining the structural differences between PrP isoforms might enable
scientists to synthesize a PrPSc-specific antibody probe or aptamer, opening
the door to the development of a TSE diagnostic tool. Antibody probes are
increasingly being used to detect infectious agents in tissue, but their appli-
cation to prion detection is limited because no independently validated
antibody binds exclusively to PrPSc without prior digestion of PrPC. Of note,
two different groups of investigators have reported separate antibodies spe-
cific to PrPSc (Korth et al., 1997; Paramithiotis et al., 20031.
Many of the tests for detection of PrPSc use antibody probes, as de-
scribed in Chapter 4. Most tests, however, must use proteinase K to distin-
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62
ADVANCING PRION SCIENCE
guish prpC from PrPSc. Proteinase K digestion reduces the already miniscule
amount of material usually available for prion detection. The committee
looks forward to the development of new test methods that exclude pro-
teinase K.
Defining the prion structure could also reveal structure-based pheno-
typic differences among prion strains. This information would be impor-
tant because it is thought that prpC binds to PrPSc before it is converted into
PrPSc (Caughey, 20021. If the structure of the prion strain differs too greatly
from the host's PrPC, binding may occur, but conversion will not (Bessen et
al., 19951. Defining the structures of prpC and PrPSc at the sites where they
interact during binding and conformational change would support the de-
velopment of molecules to block those interactions.
Since prions are largely insoluble, it is particularly difficult to study
their structures with standard proteomic tools. A newer technique called
solid-state nuclear magnetic resonance (NMR) overcomes the solubility
problem and is in the early stages of application to research on the three-
dimensional structure of prions (Laws et al., 2001; Wemmer, 20021. In
addition, electron crystallography is being used to probe the two-dimen-
sional structures of PrPSc crystals (Wille, 20021. Nobel Laureate Kurt
Wuthrich produced three-dimensional models of prpC using liquid-phase
NMR experiments (Zahn et al., 20001. Nevertheless, the research commu-
nity must do much more to obtain a comprehensive understanding of the
structural differences between infectious and noninfectious PrP.
MOLECULAR MECHANISMS OF PRION REPLICATION
It is believed that both the conversion of cellular PrP to PrPSc and the
accumulation of prions require the assistance of one or more molecules
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BASIC BIOMEDICAL RESEARCH ON TSEs
63
(Caughey, 2001~. These ancillary or chaperoning factors could serve as sur-
rogate markers for prion detection and as drug targets for TSE therapeutics
and prophylaxes. Therefore, it is critical that the NPRP fund research de-
signed to identify the molecules that facilitate PrPSc formation and accumu-
. . .
anon In salvo.
Experiments have demonstrated that the chaperone proteins GroEL and
hsplO4 can stimulate the cell-free conversion reaction, as can sulfated gly-
cans (Won" et al., 2001) and partial denaturants (DebBurman et al., 19971.
Other chaperone proteins thought to modulate PrP conversion include
hsp73 (Tatzelt et al., 1995), members of the hsp60 class (DebBurman et al.,
1997; Edenhofer et al., 1996; Stocke! and HartI, 2001), and BiP (Tin et al.,
2000~. There are at least a half-dozen apparently natural PrP ligands or
conversion modulators: copper (II) (Hornshaw et al., 1995), the laminin
receptor (Weiss and Randour, 2002), laminin (Graner et al., 2000), stress-
induced protein 1 (Zanata et al., 2002), and nucleic acids (Cordeiro et al.,
2001; Gabus et al., 2001; Nandi and Leclerc, 19991.
The molecule or molecules associated with prion conversion may be
easier to detect than prions themselves. For instance, there may be a known
antibody that binds specifically to a chaperone protein involved with PrP
formation or accumulation. Ancillary or chaperoning factors could poten-
tially amplify PrPSc, helping to overcome current limits to prion detection.
A related goal of NPRP should be to fund research aimed at isolating
the multiprotein complexes that contain priors. Such studies might identify
new cofactors that are important in the formation and stabilization of PrPSc
and infectivity. For instance, molecules such as sulfated glycosaminogly-
cans appear to be associated with PrPSc deposits in viva (Snow et al., 1990)
and may play a role in their formation in viva, as can be the case with a
variety of other amyloid protein deposits. Further understanding of the iden-
tities and roles of PrPSc-associated molecules might suggest new therapeutic
and diagnostic approaches.
MECHANISMS OF TSE PATHOGENESIS
If better diagnostics are to be developed, much more understanding of
the nature and dynamics of prion infection must be gained. Research on the
pathogenesis of TSEs holds the keys to such understanding. Researchers,
clinicians, and public health officials must know which tissues are infec-
tious and when, what mechanisms are involved when the infectious agent
enters and disseminates in the body and then invades the brain, what causes
cellular toxicity (priors, prions plus another molecular species, or a totally
different molecular entity), what the mechanisms are by which the toxic
events lead to cellular dysfunction and clinical symptoms, how the infec-
tious agent spreads from host to host, and what features of the host deter-
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64
ADVANCING PRION SCIENCE
mine susceptibility to infection. Understanding of these matters will lead to
improved characterization of diagnostic targets, better diagnostic strate-
gies, greater target discrimination, and improved diagnostic sensitivity and
... .
spec~c~ty.
The pathogenesis of TSE agents may vary among strains and hosts, and
the same host may be infected by more than one strain. For example, we
cannot assume that known TSE strains are pure or uniform. In mouse as-
says, a given strain (phenotype) has characteristic histopathological fea-
tures and incubation periods. Yet in a recent study, transgenic mice express-
ing human PrP and inoculated with the BSE agent manifested not only the
expected vCJD phenotype, but also, surprisingly, the sCJD phenotype
(Asante et al., 20021. The researchers suggest, in general, that TSE infec-
tions may involve multiple strains resulting in variable host responses. More
specifically, they postulate that some of the sCTD occurring in the United
Kingdom and elsewhere may be due to BSE exposure. A better understand-
ing of prion strains and subtypes and their differential pathogenesis, there-
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BASIC BIOMEDICAL RESEARCH ON TSEs
65
fore, is crucial. In addition, the conditions under which a TSE agent may
exist in an asymptomatic carrier state within the host should be explored.
The general factors affecting host resistance are known and include
genetic, environmental, and agent-specific characteristics. Their interrela-
tionships are poorly understood, however. A recent experiment by lean
Manson and colleagues demonstrates this point. Manson's group showed
that mice expressing PrP with the LeulO1 mutation, corresponding to hu-
man GSS, did not spontaneously develop clinical or subclinical prion dis-
ease (Manson et al., 19991. However, their experiment also showed that
this disease-associated mutation differentially increased susceptibility to in-
fection with human GSS-derived infectivity and simultaneously decreased
susceptibility to several mouse scrapie strains. Thus, the study demonstrated
that mutant PrP expression was an important genetic susceptibility factor,
although it was unable to generate spontaneous infectivity in viva alone.
Continued research in this area will lead to a firmer understanding of how
genetic factors interact with the TSE agent and environmental factors.
All pathogenetic studies must be interpreted in their specific contexts, a
requirement that makes the development of diagnostics more difficult. At
the same time, what investigators learn about the pathogenesis of one prion
disease will yield information relevant to the understanding of other prion
diseases.
Studies raising questions about presumed pathogenic mechanics are
important in stimulating new theories and new scientific inquiry. For ex-
ample, a new team of investigators studying transmissible mink encephal-
opathy (TME) in hamsters showed that the agent proceeded along cranial
nerves in the tongue directly to the brain, bypassing the intestinal route
(Bartz et al., 20031. This finding suggests that prions could enter the body
through oral lesions on the tongue, then migrate to the central nervous
system through cranial nerves. Bartz and colleagues also showed that the
TME agent, if injected into the brain of an uninfected hamster, would travel
down to the tongue in a retrograde fashion. This finding generated some
concern that BSE-infected cattle or CWD-infected cervids may harbor the
infectious agent in their tongues. However, similar studies must be done to
determine whether the agents of BSE and CWD appear in the tongues of
infected bovines and cervids, since the aforementioned work involved a
different agent (that of TME) as well as a different host animal (hamster).
The possibility that cranial nerves may serve as fast tracks for the TSE
agent to enter the central nervous system was recently heightened by the
discovery of PrPSC in the olfactory tracts of nine patients with sCJD, sug-
gesting that the olfactory pathway might serve as a portal of entry for the
natural transmission of sCTD (Zanusso et al., 20031. This could have impli-
cations for iatrogenic transmission of the disease.
Understanding TSE pathogenesis at the cellular level essential for the
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66
ADVANCING PRION SCIENCE
development of effective diagnostic tools and therapeutic agents requires
knowledge of the mechanisms of toxicity. TSE researchers do not know
precisely how and where cellular toxicity occurs. Although most experts
believe toxicity occurs at or near the cell membrane, new research in this
area is challenging current theories. For example, studies by Ma and col-
leagues seem to indicate that cellular toxicity may occur in the cytoso! due
to an aggregation of misfolded proteins that accumulates by retrograde
transport through the endoplasmic reticulum (Ma and Linguist, 2002; Ma
et al., 20021. Although these studies need validation, and have even been
disputed (Drisaldi et al., 2003), they open up new research possibilities.
The study of TSEs should not be limited to mammalian species. Much
can be learned from the study of prions found in other, nonmammalian
organisms. For example, the prions found in fungi have been studied exten-
sively, including two prions of the yeast Saccharomyces cerevisiae. In 1994,
those two priors, fURE3] and EPSI+], were discovered to be infectious forms
of their normal proteins, Ure2P and Sup35p, respectively (Wickner, 19941.
The first prior-inducing domain was defined, and the protease resistance of
the Ure2P in fURE3] prion strains gave the first hint of the mechanism
involved (Masison and Wickner, 19951. Soon after, it was discovered that,
as in mammals, multiple strains of yeast prions can exist (Derkatch et al.,
19961. Ter-Avanesyan's group was the first to show that the EPSI+] prion is
a self-propagating aggregation of Sup35p in viva and in vitro (Paushkin et
al., 19971.
Later that year, King and colleagues showed that the prion domain of
Sup35p could form amyloid in vitro (King et al., 19971. Then Glover and
colleaguesshowed that the full length of Sup35p could form filaments in
vitro having characteristics of amyloid that were stimulated by extracts of
EPSI+] cells, but not the extracts of Epsi-] cells (Grover et al., 19971. Also in
1997, a prion was found in the filamentous fungus Podospora anserine
(Coustou et al., 19971. Another prion, EPIN+], of the Rnqlp protein of S.
cerevisiae was reported in 2001 (Derkatch et al., 20011.
Work with these prions has been highly rewarding. The experiments
with S. cerevisiae described above provided the first evidence that chaper-
one proteins are involved in prion propagation (Chernoff et al., 19951. Ad-
ditionally, the Mksl protein was shown to be necessary for generation of
the fURE3] protein (Edskes and Wickner, 20001. Also, the Ras-cyclic AMP
pathway was found to negatively regulate generation of the fURE3] prion
protein (Edskes and Wickner, 20001.
The presence of one prion in a cell can promote the generation of an-
other (Derkatch et al., 20011. Amyloid of the HET-s protein formed in vitro
was shown to be infectious for fungal colonies, whereas nonspecific aggre-
gates or the soluble form of the protein had no effect (Maddelein et al.,
20021. Efforts to replicate this process in mammals have not yet been suc-
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BASIC BIOMEDICAL RESEARCH ON TSEs
67
cessful. In addition, investigators have shown that artificial prions can be
constructed by using a prion domain of one protein and a reporter domain
of another (Li and Linguist, 2000~. Another landmark discovery from a
study of S. cerevisiae that used tHet-s] was that prions can be advantageous
to the prion host (Coustou et al., 19971.
In view of the close parallels between yeast and mammalian priors,
scientists could potentially use yeast to screen for prior-curing agents that
might aid in the development of a TSE treatment. For example, yeast prions
can be cured by growth on low concentrations of guanidine, an inhibitor of
the chaperone HsplO4 (Bach et al., 2003;Jung et al., 2002; Tuite et al.,
19811. Also, fragments of yeast prion proteins cure the respective prion
(Edskes et al., 19991.
Drosophila and Caenorhabditis elegans have also proved to be superb
models for the study of a variety of cellular and molecular processes
(Hariharan and Haber, 2003) and should be exploited to study prion dis-
eases. These organisms have recently been used to mode! several human
neurodegenerative conditions, including Parkinson's disease, tauopathies,
and polyglutamine disorders. These mode! systems may clarify the basis for
neurodegeneration in prion diseases, as they have in other neurodegenerative
processes.
PErYSIOLOGICAL FUNCTIO N OF prpC
Because the primary structure of PrPSc is virtually identical to that of
normal PrP, understanding as much as possible about prpC would be very
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68
ADVANCING PRION SCIENCE
helpful in the development of TSE diagnostic tests. A successful test must
discriminate between these two closely related molecules. Moreover, under-
standing the normal role of prpC may reveal associated molecules and path-
ways that are appropriate detection targets. It remains unclear whether the
basis for nerve cell dysfunction and death in prion disease is related to the
toxicity of PrPSc, to the loss of function of prpC as a result of its conversion
to PrPSc and its aggregation during a prion infection, or to other factors.
Recommendation 3.1: Fund basic research to elucidate (1) the struc-
tural features of priors, (2) the molecular mechanisms of prion rep-
lication, (3) the mechanisms of pathogenesis of transmissible
spongiform encephalopathies, and (4) the physiological function of
PrPC. [Priority 11i
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Representative terms from entire chapter:
basic biomedical
