Current Medicinal Chemistry–Immunology, Endocrine & Metabolic Agents Volume 3, No. 2, 2003
Contents
Transmissible
Spongiform Encephalopathies (Prion Diseases)
Guest
Editors: Xuemin Ye and Richard
Identification and Detection of Transmissible
Spongiform Encephalopathies
Pp. 95-111
X.
Ye , R. I. Carp , H. C. Meeker and A.
C. Scallet
Immunological Therapeutic and Imaging
Approaches for Prion Disease
Pp. 113-118
Marcin
Sadowski and Thomas Wisniewski
The Role of Components of the Lymphoreticular
System in Transmissible Spongiform Encephalopathy Pathogenesis and
Neuroinvasion Pp. 119-135
D.S.
Spinner , X. Ye, R.I. Carp and R.J. Kascsak
Prion Protein Misfolding and Brain
Degeneration Pp. 137-147
Claudio
Hetz , Sergio Benavent , Sylvain Bieler
and Claudio Soto
Effects of Transition Metals in the Conversion
Mechanism of Prion Protein and in the Pathogenesis of Prion Diseases Pp. 149-160
Nam-Ho
Kim , Jae-Il Kim , Richard I. Carp and
Yong-Sun Kim
Gender, Hormones and the Transmissible
Encephalopathies Pp. 161-169
O.O.
Abiola and
Pathophysiology of Transmissible Spongiform
Encephalopathies Pp. 171-184
A.C.
Prion Diseases: Time for a Therapy ? Pp. 185-197
Gianluigi
Forloni , Maria Rosaria Varì, Laura Colombo, Orso Bugiani , Fabrizio
Tagliavini and Mario Salmona
From Chemical Drug to Immunotherapy: New Approaches
for the Treatment of Prion Diseases Pp. 199-205
Veronique
Perrier , Carole Crozet , Jerome Solassol
and Sylvain Lehmann
Abstracts
[Back to top] Identification and Detection of Transmissible
Spongiform Encephalopathies
X.
Ye , R. I. Carp , H. C. Meeker and A.
C. Scallet
Scrapie is a slowly
developing transmissible spongiform encephalopathy (TSE) occurring naturally in
sheep and goats. At present, there is no efficient antemortem diagnostic test
for TSEs. Electroencephalograms (EEGs), electrocardiograms (ECGs),
magnetic-resonance imaging (MRI), positron emission tomography (PET), single
photo emission computed tomography (SPECT), as well as conformation-dependent
immunoassay (CDI), which show patterns characteristic of prion diseases, can
obtain diagnostic information for TSEs. Other methods include testing
cerebrospinal fluid for the presence of 14-3-3 proteins, Fourier transformation
infrared spectroscopy (FTIR), brain biopsy, nasal biopsy and tonsil biopsy. For
better TSE diagnosis, most TSEs need to be confirmed by the presentation of
abnormal prion protein by Western blot, ELISA immunochemical methods, or
immunocytochemistry methods, or by bioassays, a more sensitive but
time-consuming method, which involves inoculating suspended homogenates into
susceptible hosts and waiting for a long incubation period to conclude. An
antemortem diagnostic test for TSEs can be done from spleen or lymph node biopsy
by evaluating PrPSc presence. Since it has been suggested that the buffy coat
of TSE animals may carry infectivity, a method for presymptomatic diagnosis of
TSE from blood is clearly possible and desirable. At present, antibodies
against prion protein cannot distinguish normal prion protein (PrP C)
and abnormal prion protein (PrPSc); there is no reliable antibody to
detect PrPSc only. In this review, we propose that the development
of gene chips and/or protein chips for assays of TSE diseases might prove very
useful. A great deal of basic research on TSE diagnosis, prevention, and
treatment remains to be conducted.
[Back to top] Immunological Therapeutic and Imaging
Approaches for Prion Disease
Marcin
Sadowski and Thomas Wisniewski
Currently there is no
effective treatment or prophylaxis against prion diseases. Although sporadic
forms of this disease are relatively rare, the incidence of the transmissible
prionoses is rising as a result of the exposure of Western European populations
to bovine spongiform encephalopathy. It has been recently demonstrated in
animal models that active or passive immunization may delay the onset of
disease or even protect from the occurrence of symptoms if started prior to
prion replication involving the central nervous system. Results of these animal
studies suggest that development a vaccination approach for humans is feasible
within the near future. Another aspect of prion diseases, potentially limiting
the practical use of the vaccine, is lack of diagnostic tests detecting
infected, non-symptomatic subjects. This can partially be overcome using high
field magnetic resonance imaging (MRI), which in animal models is capable of
detecting signal alterations in the brain before the onset of symptoms. Another
potential way to improve the sensitivity and specificity for prion infection
diagnosis is using ligands specifically targeting the b-sheet structure of PrPSc or anti-PrP
antibodies. These can be coupled either with paramagnetic agents or radioisotopes
making PrPSc detectable using MRI or scintigraphy respectively. Successful
development of such ligands has been demonstrated for Alzheimer’s disease and
is currently being studied for prionoses.
[Back to top] The Role of Components of the Lymphoreticular
System in Transmissible Spongiform Encephalopathy Pathogenesis and
Neuroinvasion
D.S.
Spinner , X. Ye, R.I. Carp and R.J. Kascsak
The transmissible
spongiform encephalopathies (TSEs), or prion diseases, are a group of
neurodegenerative disorders that affect a variety of mammalian species. These
diseases include scrapie in sheep, bovine spongiform encephalopathy (BSE) in
cattle, chronic wasting disease (CWD) in elk and deer, and Creutzfeldt-Jakob
disease (CJD) in humans. Recently, the transmission of BSE to humans has led to
the formation of a new class of human TSE known as new variant CJD (nvCJD).
Indicative of TSEs in vivo is the presence of an abnormal conformer of the
naturally occurring host protein PrPC, referred to as PrPSc.
Expression of PrPC by a potential host is an absolute requirement
for a TSE infection to progress to clinical disease. While TSE agents
ultimately affect the brain, for optimal pathogenesis and neuroinvasion
kinetics most strains require functionally intact lymphoid organs. Accordingly,
a majority of the data compiled to date on TSEs indicates that bolstering
lymphoreticular function potentiates the ability of most agent strains to
induce symptomatology in a given host. Attenuation of such functioning by
various means, conversely, can severely diminish or, for some strains of agent,
completely ablate pathogenesis and neuroinvasion. In this review we examine the
cellular and physiological bases for these findings and explore possible underlying
mechanisms of TSE pathogenesis. In addition, we examine new lines of research
required to complete the puzzle of how TSEs utilize cells of the
lymphoreticular system to their advantage and complete the neuroinvasion
process.
[Back to top] Prion Protein Misfolding and Brain
Degeneration
Claudio
Hetz , Sergio Benavent , Sylvain Bieler
and Claudio Soto
Prion diseases are
rare fatal neurodegenerative diseases of humans and other animals. The hallmark
pathological features of TSEs are the spongiform degeneration of the brain,
extensive neuronal loss, astrogliosis, and accumulation in the brain of a
misfolded form of the prion protein (PrP). It has been proposed that PrP
conformational changes may lead to the loss of physiological function of PrP or
to acquisition of a neurotoxic activity by the misfolded protein, which may
promote directly neuronal dysfunction. Alternatively, misfolded and aggregated
prion protein may cause disease by inducing a chronic inflammatory reaction in
the brain, leading to extensive brain damage mediated by reactive astrocytes
and activated microglia. The aim of this article will be to review the
different mechanisms that could relate PrP misfolding with brain degeneration
and the emergence of TSE.
[Back to top] Effects of Transition Metals in the
Conversion Mechanism of Prion Protein and in the Pathogenesis of Prion Diseases
Nam-Ho
Kim , Jae-Il Kim , Richard I. Carp and
Yong-Sun Kim
Transmissible
spongiform encephalopathies (TSEs) or prion diseases are fatal
neurodegenerative disorders in humans and animals, and include
Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy
(BSE) in cattle, and scrapie in sheep. All forms of prion diseases have common
features: spongiform degeneration of the central nervous system, reactive
gliosis, neuronal loss and in some cases, formation of amyloid plaques.
Conversion of the host cellular prion protein (PrPC) into an
abnormal, protease-resistant and infectious isoform (PrPSc) is
believed to be a central molecular basis of neurodegeneration in prion
diseases. Although there are vigorous disputes about the conversion mechanisms
of PrPC to PrPSc, considerable evidence suggests that
various factors such as molecular chaperones and transition metals may be
closely associated with the PrP conversion process and that disturbance in the
homeostasis of several transition metals may play an important role in the
pathogenic mechanisms of prion diseases. Here, we briefly review and discuss
current topics about the effects of transition metals in the PrP conversion
mechanisms and in the pathogenesis of prion diseases.
[Back to top] Gender, Hormones and the Transmissible
Encephalopathies
O.O. Abiola and S.A. Whatley
We have recently
observed a link between gender and the species barrier in the transmission of
TSEs to mice. Gender effects are also observed in other age dependent
neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s
disease (PD), which may suggest the identity of common pathogenic pathways.
While these effects could be caused by several factors, the most obvious
explanation is that they are mediated by gender-specific hormonal influences.
This review covers
host factors that influence the transmission of TSEs as they relate to gender.
The relationship between the phenomenology of prion disorders and other
neurodegenerative diseases is discussed, which anticipates a role for sex steroid
hormones in the control of the mechanisms of neurodegeneration.
[Back to top] Pathophysiology of Transmissible Spongiform
Encephalopathies
A.C. Scallet , R.I. Carp and X. Ye
Transmissible
spongiform encephalopathies (TSEs) are an intriguing group of diseases that are
a challenge to rational drug design for treatment or prevention by medicinal
chemists and pharmacologists. There are similarities between brain pathological
changes caused by excitatory amino acids (EAAs) toxicity and by TSE infection.
Neurons mediating the neuroendocrine functions of the hypothalamus as well as
Purkinje cells of the cerebellum are targets for damage by TSEs and EAAs. Both
EAAs and TSE agents cause astrocytosis. TSEs commonly feature swollen
astrocytes either containing abnormal prion proteins (PrPSc) or
located immediately adjacent to PrPSc deposits in the neuropil.
Antigenic properties of the PrPSc may stimulate the release of
nearby microglial and astrocytic cytokines, resulting in dysfunction and damage
to elements of the neuropil. Such swollen astrocytes also commonly occur
following exposure to a number of other neurotoxicants such as EAAs. Early
neuropathological changes in scrapie involve primarily astrocytes and nerve
terminals, but not nerve-cell bodies or spongiform changes. These data suggest
that the initial events in the pathophysiology of TSEs may be the astrocytic
response to PrPSc accumulation, leading to NOS/free radical damage
to nearby nerve terminals. We will review the similarities in brain
pathological changes caused by TSEs and EAAs. We suggest that the end-stage
neuropathology produced by TSEs has many of the characteristics of EAA-mediated
neuronal necrosis, a well-established final common pathway of neurodegeneration
from a variety of neurotoxicants. The cytoprotective effects of the antagonists
of the NMDA receptor-channel complex such as memantine (1-amino-3,5-
dimethyladamantane; MEM), MD-ADA (1-N-methylamino-3,5-dimethladamantane) or
dizolcipine (MK-801, (+)-5- methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine
malate) will be considered.
[Back to top] Prion Diseases: Time for a Therapy ?
Gianluigi Forloni , Maria Rosaria Varì, Laura Colombo, Orso Bugiani , Fabrizio Tagliavini and Mario Salmona
Prion diseases are
transmissible neurodegenerative disorders of humans and animals for which no
effective treatment is available. Conformationally altered, proteaseresistant
forms of the prion protein (PrP), termed PrPsc, are critical for disease
transmissibility and pathogenesis, thus representing a primary target for
therapeutic strategies. Different approaches affecting the clearance of PrPsc,
inhibiting or preventing its conformation change are currently under investigation.
Some compounds antagonize prion propagation in cellular and/or animal models of
the disease. These molecules include polyanions, polyene antibiotics,
tetrapyrroles, branched polyamines and compounds termed 'beta-sheet breakers'
whose direct target its the abnormal conformational change for PrPsc. The
suitability of these compounds for therapy is limited, primarily because they
cannot cross the blood-brain barrier (BBB) and/or show severe toxicity. A
variety of drugs already used for treatment of unrelated human diseases and
known to penetrate the BBB have now been screened. The tricyclic derivatives of
acridine and phenothiazine inhibit PrPsc formation in scrapie-infected
neuroblastoma cells, confirming earlier reports on anti-prion activity of these
compounds. In addition, activation of the immune system has been proposed to
increase the clearance of PrPsc and reduce the prion infectivity and antibodies
can exert antiaggregation activity. We showed that tetracyclines reverse
abnormal physicochemical properties and abolish the neurotoxicity of PrP
peptides in vitro. These compounds interact with PrPsc from brain tissue of
BSE-affected cattle and patients with new-variant Creutzfeldt-Jakob disease
(vCJD). Syrian hamsters injected with tetracycline-treated inoculum showed a
significant delay in the onset of clinical signs of disease and prolonged
survival time. When tetracycline was pre-incubated with a high dilution of the
scrapie-infected inoculum, one third of the hamsters did not develop disease.
These conformation-based approaches appear to hold the most promise for prion
diseases and for the neurodegenerative disorders associated with protein
misfolding. Although several classes of compounds offer anti-prion action their
use in clinical practice is limited by the fact they have little or no efficacy
at the onset of the disease. Thus, the discovery of more efficient drugs must
run in parallel with the development of diagnostic tests to identify TSE
earlier.
[Back to top] From Chemical Drug to Immunotherapy: New
Approaches for the Treatment of Prion Diseases
Veronique
Perrier , Carole Crozet , Jerome Solassol
and Sylvain Lehmann
Transmissible spongiform
encephalopathies (TSEs) also called prion diseases are fatal neurodegenerative
disorders of humans and animals which are unique as their origin can be
infectious, genetic or sporadic. More than 80% of TSE patients have sporadic
cases, 15% have familial forms and 5% iatrogenic forms. In humans, TSEs are
represented by Creutzfeldt Jakob disease (CJD), Gerstmann-Sträussler-Scheinker
syndrome, Fatal Familial Insomnia and Kuru. In animals, the prominent prion
diseases are scrapie of sheep and goats, bovine spongiform encephalopathy (BSE)
of cattle and chronic wasting disease (CWD) of deer and elk. A critical event
in TSEs is the accumulation in the central nervous system (CNS) of an
abnormally folded protein, PrPSc, the protease-resistant isoform of
a normal cellular protein encoded by the host and called PrPC. Until
now, PrPSc isoform represented not only the best molecular marker of
prion diseases but also a favorite target for therapeutic strategies.
During the last decade
studies on prion diseases have taken a new dimension with the BSE crisis in
Europe and the emergence of a new variant of Creutzfeldt-Jakob disease (vCJD)
linked to the BSE agent. Currently, no effective therapy exists for patients
suffering from a clinically manifest prion disease. In addition, the
multiplicity of TSE’s origins and clinical forms emphasizes the difficulties of
a therapeutic intervention. Indeed, it is likely that sporadic CJD which are
diagnosed lately during the course of the disease request the development of a
therapeutic approach that is different from that of familial prion diseases due
to mutation in the PrP gene. Diagnosis, origin and stages of the disease are
critical factors that should orient studies towards the development of adapted
therapeutic approaches. In this article, we will review the anti-prion drugs
that were identified up to now.