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Prion dimers: a deadly duo
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fatal) if an individual is homozygous at codon 129 rather than heterozygous. This peculiar sensitivity of PrP homozygotes to prion disease is shown even more dramatically in sporadic CJD. PrP genotype analysis of these individuals has shown that the great majority (-95%) are homozygous (MM or VV) at codon 129, whereas only 50% of the general population are homozygous at this site 12. Thus, heterozygosity (MV) at codon 129 seems to be protective against sporadic CJD.
John Hardy
he hypothesis that any disease T might be caused by an infec- Priori dimers:a deadlyduo? tious protein might appear ridiculous. However, much circumstantial evidence has suggested In another experiment, mice that prions - abnormal derivatives were transfected with a hamster of the host-encoded prion protein PrP gene. These transfected (PrP) - might cause the spongi- mice, unlike normal mice, are exform encephalopathies Creuzfeldt- quisitely susceptible to infection Jakob disease (CJD), Gerstmann- with hamster-derived prions 7'8. Str~iussler-Scheinker syndrome Furthermore, when such mice are (GSS) and kuru in humans, and infected with hamster-derived scrapie, bovine spongiform en- prions, they develop hamster-style cephalopathy and related diseases pathology and produce hamster prions: when the mice are infected in animals (reviewed in Ref. 1). The key observation was that with mouse-derived prions, they hereditary forms of the human develop mouse-style pathology and illnesses (which make up about produce mouse prions. The 10% of CJD cases and most GSS simplest explanation of these cases) were co-inherited with results is that the crucial event in mutant alleles of the PrP gene 2'3. infection is the interaction between Now, experiments in which mutant the infecting prions and the hostPrP genes have been transfected encoded PrP: such interactions into mice demonstrate that a prod- had previously been postulated on uct of the PrP gene is the in- the basis of genetic data in mice fectious agent. PrP gene analysis showing that disease incubation of individuals with CJD and GSS time was controlled at the PrP supports a hypothesis implicating locus in mice 6. PrP-PrP interactions as the central pathogenic process under- Human prion disease The animal experiments relying the disorders. ferred to above suggest that PrPPrP interactions are the central Experiments with prions event in disease pathogenesis: using transgenic mice In a remarkable series of exper- PrP genotype data in human disiments, Prusiner and colleagues ease supports this suggestion. Many pathogenic mutations have shown that a PrP gene product is the pathogenic agent leading to human prion disease and that the PrP protein of the host have been described 1. In addition, is the major determinant of the there are two alleles of the PrP gene in the general population: one species barrier to infection. In the crucial experiment, mice with a methionine at codon 129 (M were transfected with a sequence allele; 70%), and one with a valine similar to a pathogenic human vari- at this position (V allele; 30%) 9. ant of the PrP gene (with a mu- These variants are not pathogenic, tation at codon 102). These mice although individuals with a W developed scrapie-like disease 4, genotype seem to be particularly and isolates derived from these susceptible to prion disease inmice were used to infect other fection9. In a large English family mice (preliminary data reported in with hereditary prion disease Ref. 5). Thus, an infectious agent (some of whom had been diaghad been 'created' by the simple nosed as suffering from CJD, some substitution of a single amino acid from GSS and some from Alzin PrP. This experiment should heimer's disease1°), a pathogenic finally dispel the doubts of those mutation has occurred on an M who believed that a nucleic acid allele. Within this pedigree, indi(i. e. an unconventional virus) must viduals whose other allele is also M be involved in the pathogenic pro- have a disease onset of <40 years, cess, since such an agent must but individuals whose other allele is now be postulated as ubiquitous in V have an onset of >40 years 11. order to explain the occurrence of This suggests that the interaction the human hereditary disease and between the pathogenic PrP allele the experiments with transgenic and the other PrP allele is more mice 6. efficient (and thus, more rapidly TINS, Vol. 14, No. 10, 1991
Deptof Biochemistry andMolecular Genetics,St. Mary's HospitalMedical Schoel,London W2 1PG,UK.
The induced PrPC-PrP sc hypothesis These data fit most comfortably with a hypothesis having the fop lowing components 1. (1) PrP exists as a dimer. (2) PrP can exist in one of two forms - a cellular
prp C
® p r p SC
X2
[ [ Fig.
1.
X2
Postulated interactions between "cellular' and
'disease' forms of prions that result in prevalence of the pathogenic form.
© 1991. EPsevierSciencePublishersLtd, (UK) 0166- 2236/91/$02.00
423
against sporadic CJD (see Fig. 1). The most likely cause of sporadic CJD would seem to be either somatic PrP gene mutations, followed by PrP sc formation and autoinfection, or stochastic conversion of PrP c to PrP sc, followed by autoinfection. While this hypothesis explains most of the available data, many questions remain; in particular, the existence of scrapie 'strains' needs to be re-examined in the light of the recognition of the occurrence of different alleles of PrP. In addition, the rapid progress of recent work has come about through the application of molecular genetics to the PrP gene structure. In order to understand fully the pathogenesis of the disease, equivalent progress must be made in the understanding of the structure of the PrP isoforms. Then, the molecular nature of the conformation change of PrP can be elucidated. Whatever the outcome, it would seem likely that these most enig-
matic of primary neurodegenerative diseases will be the first for which we will understand the molecular nature of their aetiology and pathogenesis.
Inductive eventsin the neural tube
notochord leads to the development of an abnormal neural tube that lacks a normal floor-plate structure s'~. The addition of an ectopic notochord, either by experimental grafting1°'11 or because of developmental abnormalities 1°'12, can induce the formation of an extra ectopic floor plate (as assayed histologically) and the proliferation and differentiation of extra neurons with properties of ventral motoneurons (namely, acetylcholinesterase activity and peripheral axons). This inductive effect appears to be both time and distance dependent in the chicken embryo. At early stages and at close proximity (<30 gin) to the neural tube, notochord grafts induce an ectopic floor plate with extra neurons on either side of this floor plate. At later stages or at greater distances (30-80 gin), however, notochord grafts induce the extra neurons, but not a floor plate m'~3. An interesting feature of this dual effect of notochord grafts is that the induction of floor plate involves an inhibition of proliferation, while the induction of extra neurons involves enhanced proliferation. A long-standing difficulty with studies such as these is the unequivocal identification of the cell types being induced. Yamada et
isoform (prpc), and a pathological (scrapie) isoform (prpSc). These forms do not differ in their composition, but in their conformation. (3) PrP dimers are in equilibrium with PrP monomers: if a dimer is formed of a PrP sc and a PrP c, the PrW is converted to PrP sc. This hypothesis explains infectivity, since the addition of PrP sc will convert the host-encoded PrP c to PrP sc. Hereditary prion disease can be explained by postulating that the pathogenic mutations lead to PrP variants that stochastically switch from PrP c to PrP sc and thus initiate the disease process. PrP homodimers would be expected to be more energetically favoured than PrP heterodimers (symmetry considerations would predict that this would be so). This favouring of homodimers over heterodimers explains the species barriers for infection, the age of onset variability in the human hereditary disease, and the protection of PrP heterozygotes
Joel C. Glover Dept of Physiology, Institute of Basic Medical Sciences, University of Oslo, Blindern, N-0317 Oslo, Norway.
424
he formation of the vertebrate nervous system during emT bryogenesis is contingent on a close association between the invaginating chordamesoderm and the overlying ectoderm. As a result, the ectoderm is determined to become the neuroectoderm precursor of the nervous system. In the absence of this association, the ectoderm acquires an epidermal fate 1'2. This sort of interaction, in which one tissue directs another to differentiate in a way it otherwise would not, is called induction. Inductive interactions are commonplace during embryogenesis. They are responsible for generating the chordamesoderm itself prior to gastrulation, and at later embryonic stages they play a pivotal role in determining different cell types in essentially all organ systems (for a fine overview of the role of induction in organogenesis, see Ref. 3). In the developing nervous system, for example, the neural plate (and later the optic vesicle) set up a series of inductions in adjacent ectoderm that generates the lens and cornea, while the hindbrain neural tube induces adjacent ectoderm to form the otic placode (from which is derived the vestibular and auditory
apparatus and associated ganglia). Thus, the induction of the neuroectoderm by chordamesoderm is only one link in a cascade of inductive interactions involved in determining neural structures and associated tissues. Some recent studies in chicken4'5, quail6 and fish 7 embryos provide exciting new details about how induction patterns the developing nervous system. After the neuroectoderm has been induced, there is a continued proximity between chordamesoderm (in the form of the notochord) and neuroectoderm - initially in the form of the neural plate and later as the neural tube. As neural cells proliferate, the neural tube begins to exhibit an obvious regionalization in the transverse plane. In the spinal cord this is manifested by the formation of a ventral floor plate and a dorsal roof plate, and the differentiation of specific cell groups, such as the lateral motor columns that lie on either side of the floor plate at a characteristic distance (Fig. 1). It has been known for some time that the notochord is involved in establishing at least part of the spatial pattern in the neural tube. Preventing the formation of the
© 1991,ElsevierSciencePublishersLtd.(UK) 0166 2236/91/$0200
Selected references 1 Prusiner, S. 8. (1991) Science 252, 1515-1522 2 0 w e n , F. et a/. (1989) Lancet i, 51-52 3 Hsiao, K. et aL (1989) Nature 338, 342-345 4 Hsiao, K. et aL (1989) Science 250, 1587-1590 5 Marx, J. (1991) Science 251, 1022-1023 6 Hunter, N. (1991) Trends Neurosci. 14, 389-390 7 Scott, M. e t a / . (1989) Cell 59, 847-857 8 Prusiner, S. B. et aL (1990) Cell 63, 673-676 9 Collinge, J., Palmer, M. S. and Dryden, A. J. (1991) Lancet337, 1441-1442 10 Collinge, J. et al. (1990) Lancet 336, 7-9 11 Baker, H. F. etal. (1991)Lancet337, 1286 12 Palmer, M. S., Dryden, A. J., Trevor Hughes, J. and Collinge, J. (1991) Nature 352, 340-342
TINS, VOI. 14, NO. 10, 1991
news
fatal) if an individual is homozygous at codon 129 rather than heterozygous. This peculiar sensitivity of PrP homozygotes to prion disease is shown even more dramatically in sporadic CJD. PrP genotype analysis of these individuals has shown that the great majority (-95%) are homozygous (MM or VV) at codon 129, whereas only 50% of the general population are homozygous at this site 12. Thus, heterozygosity (MV) at codon 129 seems to be protective against sporadic CJD.
John Hardy
he hypothesis that any disease T might be caused by an infec- Priori dimers:a deadlyduo? tious protein might appear ridiculous. However, much circumstantial evidence has suggested In another experiment, mice that prions - abnormal derivatives were transfected with a hamster of the host-encoded prion protein PrP gene. These transfected (PrP) - might cause the spongi- mice, unlike normal mice, are exform encephalopathies Creuzfeldt- quisitely susceptible to infection Jakob disease (CJD), Gerstmann- with hamster-derived prions 7'8. Str~iussler-Scheinker syndrome Furthermore, when such mice are (GSS) and kuru in humans, and infected with hamster-derived scrapie, bovine spongiform en- prions, they develop hamster-style cephalopathy and related diseases pathology and produce hamster prions: when the mice are infected in animals (reviewed in Ref. 1). The key observation was that with mouse-derived prions, they hereditary forms of the human develop mouse-style pathology and illnesses (which make up about produce mouse prions. The 10% of CJD cases and most GSS simplest explanation of these cases) were co-inherited with results is that the crucial event in mutant alleles of the PrP gene 2'3. infection is the interaction between Now, experiments in which mutant the infecting prions and the hostPrP genes have been transfected encoded PrP: such interactions into mice demonstrate that a prod- had previously been postulated on uct of the PrP gene is the in- the basis of genetic data in mice fectious agent. PrP gene analysis showing that disease incubation of individuals with CJD and GSS time was controlled at the PrP supports a hypothesis implicating locus in mice 6. PrP-PrP interactions as the central pathogenic process under- Human prion disease The animal experiments relying the disorders. ferred to above suggest that PrPPrP interactions are the central Experiments with prions event in disease pathogenesis: using transgenic mice In a remarkable series of exper- PrP genotype data in human disiments, Prusiner and colleagues ease supports this suggestion. Many pathogenic mutations have shown that a PrP gene product is the pathogenic agent leading to human prion disease and that the PrP protein of the host have been described 1. In addition, is the major determinant of the there are two alleles of the PrP gene in the general population: one species barrier to infection. In the crucial experiment, mice with a methionine at codon 129 (M were transfected with a sequence allele; 70%), and one with a valine similar to a pathogenic human vari- at this position (V allele; 30%) 9. ant of the PrP gene (with a mu- These variants are not pathogenic, tation at codon 102). These mice although individuals with a W developed scrapie-like disease 4, genotype seem to be particularly and isolates derived from these susceptible to prion disease inmice were used to infect other fection9. In a large English family mice (preliminary data reported in with hereditary prion disease Ref. 5). Thus, an infectious agent (some of whom had been diaghad been 'created' by the simple nosed as suffering from CJD, some substitution of a single amino acid from GSS and some from Alzin PrP. This experiment should heimer's disease1°), a pathogenic finally dispel the doubts of those mutation has occurred on an M who believed that a nucleic acid allele. Within this pedigree, indi(i. e. an unconventional virus) must viduals whose other allele is also M be involved in the pathogenic pro- have a disease onset of <40 years, cess, since such an agent must but individuals whose other allele is now be postulated as ubiquitous in V have an onset of >40 years 11. order to explain the occurrence of This suggests that the interaction the human hereditary disease and between the pathogenic PrP allele the experiments with transgenic and the other PrP allele is more mice 6. efficient (and thus, more rapidly TINS, Vol. 14, No. 10, 1991
Deptof Biochemistry andMolecular Genetics,St. Mary's HospitalMedical Schoel,London W2 1PG,UK.
The induced PrPC-PrP sc hypothesis These data fit most comfortably with a hypothesis having the fop lowing components 1. (1) PrP exists as a dimer. (2) PrP can exist in one of two forms - a cellular
prp C
® p r p SC
X2
[ [ Fig.
1.
X2
Postulated interactions between "cellular' and
'disease' forms of prions that result in prevalence of the pathogenic form.
© 1991. EPsevierSciencePublishersLtd, (UK) 0166- 2236/91/$02.00
423
against sporadic CJD (see Fig. 1). The most likely cause of sporadic CJD would seem to be either somatic PrP gene mutations, followed by PrP sc formation and autoinfection, or stochastic conversion of PrP c to PrP sc, followed by autoinfection. While this hypothesis explains most of the available data, many questions remain; in particular, the existence of scrapie 'strains' needs to be re-examined in the light of the recognition of the occurrence of different alleles of PrP. In addition, the rapid progress of recent work has come about through the application of molecular genetics to the PrP gene structure. In order to understand fully the pathogenesis of the disease, equivalent progress must be made in the understanding of the structure of the PrP isoforms. Then, the molecular nature of the conformation change of PrP can be elucidated. Whatever the outcome, it would seem likely that these most enig-
matic of primary neurodegenerative diseases will be the first for which we will understand the molecular nature of their aetiology and pathogenesis.
Inductive eventsin the neural tube
notochord leads to the development of an abnormal neural tube that lacks a normal floor-plate structure s'~. The addition of an ectopic notochord, either by experimental grafting1°'11 or because of developmental abnormalities 1°'12, can induce the formation of an extra ectopic floor plate (as assayed histologically) and the proliferation and differentiation of extra neurons with properties of ventral motoneurons (namely, acetylcholinesterase activity and peripheral axons). This inductive effect appears to be both time and distance dependent in the chicken embryo. At early stages and at close proximity (<30 gin) to the neural tube, notochord grafts induce an ectopic floor plate with extra neurons on either side of this floor plate. At later stages or at greater distances (30-80 gin), however, notochord grafts induce the extra neurons, but not a floor plate m'~3. An interesting feature of this dual effect of notochord grafts is that the induction of floor plate involves an inhibition of proliferation, while the induction of extra neurons involves enhanced proliferation. A long-standing difficulty with studies such as these is the unequivocal identification of the cell types being induced. Yamada et
isoform (prpc), and a pathological (scrapie) isoform (prpSc). These forms do not differ in their composition, but in their conformation. (3) PrP dimers are in equilibrium with PrP monomers: if a dimer is formed of a PrP sc and a PrP c, the PrW is converted to PrP sc. This hypothesis explains infectivity, since the addition of PrP sc will convert the host-encoded PrP c to PrP sc. Hereditary prion disease can be explained by postulating that the pathogenic mutations lead to PrP variants that stochastically switch from PrP c to PrP sc and thus initiate the disease process. PrP homodimers would be expected to be more energetically favoured than PrP heterodimers (symmetry considerations would predict that this would be so). This favouring of homodimers over heterodimers explains the species barriers for infection, the age of onset variability in the human hereditary disease, and the protection of PrP heterozygotes
Joel C. Glover Dept of Physiology, Institute of Basic Medical Sciences, University of Oslo, Blindern, N-0317 Oslo, Norway.
424
he formation of the vertebrate nervous system during emT bryogenesis is contingent on a close association between the invaginating chordamesoderm and the overlying ectoderm. As a result, the ectoderm is determined to become the neuroectoderm precursor of the nervous system. In the absence of this association, the ectoderm acquires an epidermal fate 1'2. This sort of interaction, in which one tissue directs another to differentiate in a way it otherwise would not, is called induction. Inductive interactions are commonplace during embryogenesis. They are responsible for generating the chordamesoderm itself prior to gastrulation, and at later embryonic stages they play a pivotal role in determining different cell types in essentially all organ systems (for a fine overview of the role of induction in organogenesis, see Ref. 3). In the developing nervous system, for example, the neural plate (and later the optic vesicle) set up a series of inductions in adjacent ectoderm that generates the lens and cornea, while the hindbrain neural tube induces adjacent ectoderm to form the otic placode (from which is derived the vestibular and auditory
apparatus and associated ganglia). Thus, the induction of the neuroectoderm by chordamesoderm is only one link in a cascade of inductive interactions involved in determining neural structures and associated tissues. Some recent studies in chicken4'5, quail6 and fish 7 embryos provide exciting new details about how induction patterns the developing nervous system. After the neuroectoderm has been induced, there is a continued proximity between chordamesoderm (in the form of the notochord) and neuroectoderm - initially in the form of the neural plate and later as the neural tube. As neural cells proliferate, the neural tube begins to exhibit an obvious regionalization in the transverse plane. In the spinal cord this is manifested by the formation of a ventral floor plate and a dorsal roof plate, and the differentiation of specific cell groups, such as the lateral motor columns that lie on either side of the floor plate at a characteristic distance (Fig. 1). It has been known for some time that the notochord is involved in establishing at least part of the spatial pattern in the neural tube. Preventing the formation of the
© 1991,ElsevierSciencePublishersLtd.(UK) 0166 2236/91/$0200
Selected references 1 Prusiner, S. 8. (1991) Science 252, 1515-1522 2 0 w e n , F. et a/. (1989) Lancet i, 51-52 3 Hsiao, K. et aL (1989) Nature 338, 342-345 4 Hsiao, K. et aL (1989) Science 250, 1587-1590 5 Marx, J. (1991) Science 251, 1022-1023 6 Hunter, N. (1991) Trends Neurosci. 14, 389-390 7 Scott, M. e t a / . (1989) Cell 59, 847-857 8 Prusiner, S. B. et aL (1990) Cell 63, 673-676 9 Collinge, J., Palmer, M. S. and Dryden, A. J. (1991) Lancet337, 1441-1442 10 Collinge, J. et al. (1990) Lancet 336, 7-9 11 Baker, H. F. etal. (1991)Lancet337, 1286 12 Palmer, M. S., Dryden, A. J., Trevor Hughes, J. and Collinge, J. (1991) Nature 352, 340-342
TINS, VOI. 14, NO. 10, 1991