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From prions to prionic viruses
Medical Hypotheses
20:
139-142,1986
FROM PRIONS TO PFtIONIC VIRUSES C.I. Sandea. Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322, U.S.A. ABSTRACT The pathogens causing scrapie and other similar degenerative neurological diseases are called “prions” and classified either as It is argued viruses or, more often, as a novel class of pathogens. herein that prions are not the pathogens producing these diseases. The pathogens involved are endogencus viral systems inherited by the host. These endogenous parasites, tentatively named prionic viruses, The prions produce the prions which are horizontally transmitted. trigger the pathological manifestation of prionic viruses. INTRODUCTION The
pathogens causing slow degenerative neurological diseases like scrapie, kuru, and Creutzfeldt-Jacob disease have been designated with meaning proteinaceous particles, which is used, the term “prions”, however, without pre judgement of their physical composition ( 1,2,3).
The
numerous theories concerning the nature of these pathogens have been narrowed in the last few years to two main concepts: 1) prions are viruses (4), or 2) they are a new type of pathogens consisting mainly of protein and devoid of a nucleic acid encoding this protein (1,2,3).
Recent studies indicate that purified preparations of scrapie pathogen consist of a major sialoglycoprotein (PrP 27-30) which seems to be free of nucleic acid (5,6). The unorthodox view that prions may replicate by a protein-directed protein synthesis (7) was refuted very recently, and as expected, a “cellular gene" was shown to encode scrapie PrP 27-30 (3,8). PrP-related nRNA sequences were found at the same levels in uninfected and scrapie infected brains, and at lower levels in other tissues, suggesting that PrP 27-30, or mOre likely a related protein (PrP), is a regular cellular constituent. PrP may be converted to PsP 27-30 by a mechanism in which PrP 27-30 acts as a proteolytic enzyme regenerating itself from PrP (9). Alternatively, there may be some modifications at the genetic level (i.e. PrP DNA sequence, or its ffRNA), that are triggered directly or indirectly by the PrP 27-30, leading eventually to the production of PrP 27-30 (10,111. 139
Doubtless, underlying the nature degenerative
new experiments will soon clarify the molecular mechanism the production of PrP 27-30, but this does not mean that of the pathogens causing scrapie and the other similar neurological diseases will be also revealed (11,~). THE HYPOTHESIS
It
is’hypothesized herein that the prions defined as "small proteinaceous infectious particles which are resistant to inactivation by most procedures that modify nucleic acids” (l), are not the pathogens producing these diseases. They are phenotypic components of some endogenous viruses which are the real pathogens. These phenotypic components are transmitted horizontally triggering the parasitic manifestation of the endogenous viral organisms. The recent findings that PrP 27-30 is encoded by a DNA sequence located within the cells (this by no means qualifies it as a “cellular horizontally (predominantly gene ” 1, and that the system transmitted PrP 27-30) does not contain a nucleic acid are direct evidence supporting the above hypothesis. There is, however, a very appealing conceptual reasoning, extrapolated from what we know about the endogenous viral systems, that recommends this hypothesis even more strongly. In the following model, the nature of scrapie and of other similar pathogens is anticipated by hypothesizing their phylogenetic origin. The model shows why the nature of these pathogens is so difficult to establish, it answers reasonably some of the very prominent questions concerning their genetic features (ll), such as strain diversity and their “adaptation upon fundamentally, nothing is unorthodox about passage 11, it shows that, these pathogens, and finally it is fully testable and very simple. The cells of higher animals, and probably of most organisms, are hosts They are vertically transmitted for numerous endogenous viruses (13). vertical phylogenetic transmission), from parents to offspring (i.e. and evidently from mther cells to daughter cells during the ontogeny of multicellular organisms (i.e. vertical ontogenetic transmission). It is estimated, for example, that as much as 0.3% of the total mouse genome is represented by multiple retrovirus-related sequences (13). Their acquisition rate can be as high as one sequence per 30 gsnerations 4), and they may persist phylogenetically for many millions of RD-114, a cat endogenous virus, probably entered the cat Y ~~~rfi51i~eg~one 5-10 million years ago (15il . Occasionally, some of the endogenous viruses develop vegetatively toward the formation of their reproductive and survival systems (i.e. may infect new host cells (i.e. horizontal virions) f 16)) that transmission). Some other endogenous viruses lost their capability to form virions, thus being limited only to vertical transmission. They may express some of their genetic information in certain host cells, directing the synthesis of phenotypic components whose function is yet to be revealed (13), or their life cycle is reduced to replicative cycles of their DNA. (It should be noted, however, that technically, the DNA molecule is itself a phenotypic component of an organism, 140
This last encoding its genetic information). viruses might be defective or be under repressive the host. Consider
that
an endogenous
virus
forms “defective
group of endogenous control exerted by virions”
which do
not include the viral genome (this is a common feature of many viruses). These “defective virions” might enter a new host cell (also a common feature of many viruses), hosting parental endogenous virus, The result is more where they trigger the activation of this virus. with the potential of activating new endogenous “defective particles” Through such a phenotypic component, having horizontal viruses. controls its own pathogenic accessibility, an endogenous virus This phenotypic expression which otherwise is under host control. component might be something as simple as a single protein. It would be erroneous to consider this viral phenotypic component as being the The pathogen is within cells and through its pathological pathogen. expression the disease is produced. Therefore, if no endogenous virus is present in a cell, administration of prions would not result in the production of new prions leading to degenerative disease. CONCLUSIONS The present model may explain the phylogenetic origins and the nature of the scrapie neurological degenerative pathogens. and other Accordingly, they are endogenous viruses (we may call them ” prionic viruses”) whose horizontally transmitted phenotypic component is named prion. Therefore, the attempts to classify the prions either as viruses or a “novel class of pathogens” are misleading. Physically, biochemically, and conceptually the prions and the prionic viruses are two different entities: the “prionic viruses” are viruses, the prions are phenotypic components of those viruses. By analogy, a bacterium is considered the pathogen and not the bacterial toxin. It is difficult to understand the nature of these pathogens by identifying them with the prions, but much easier when the prionic virus is considered. For example, the prions made by a certain prionic virus might trigger the expression within the same organism of other prionic viruses, having different pathological characteristics and making strain specific prions. The result will be a population of different prions. If these prions are passaged repeatedly in the sane host species, one of the prionic virus strains might be predominantly activated such that the prion population becomes soon homogeneous. This gives the false impression that the prions adapt upon passage (2). In a similar way we may explain the observation that scrapie prions when passaged in mink maintained their ability to induce disease in goats but lost the ability to do so in mice (2). The prions produced after repeated passage in mink were different from those that were initially used; a mink specific prionic virus was predominantly activated producing prions that could further activate a goat prionic virus strain but not a mice prionic virus strain. the model presented herein explains the nature of In conclusion, pathogens producing scrapie and other similar degenerative neurological diseases, and possibly some non-neurological diseases. 141
ACKNOWLEDGMENTS I thank J. manuscript.
Railey
for
and Grace
suggestions,
Vrell
for
typing
the
REFERENCES SB. Novel proteinaceous Science 216: 136, 1982.
1.
Prusiner scrapie.
2.
Prusiner SB. 29: 1, 1984.
3.
Oesch B. et al. A cellular tein. Cell 50% 735, 1985.
4.
Rohwer RG. susceptibility
5.
Bolton the
DC. et al. scrapie
6.
Bolton Virol.
DC. et al. Scrapie 53: 596, 1985.
7.
Craig R. The theoretical possibility proteins into genes. J. Theor. Biol.
8.
Identification Chesebro B. et al. specific mRNAin scrapie-infected 315: 331, 1985.
9.
Brunory Nature.
M., Talbot B. 314: 676, 1985.
10.
Masters
C.
11.
Robertson HD. et al. 40: 725, 1983. Cell.
12.
Harris
13.
Jaenisch
14.
Quint W. et al. Mobility of endogenous ecotropic murine leukemia viral genomes within mouse chromosomal DNA and integration of a mink cell locus-forming virus-type recombinant provirus in the J.Virol. 418 901, 1982. germ line.
15.
Benveniste inheritance 456, 1974.
16.
A new theory on the Bandea CI. J. Theor. Biol. 105: 591, 1983.
T.
Prions:
infectious
Identification prion.
Perspectives
Endogenous
scrapie
Adv. Virus Res. PrP 27-30 pro-
of a protein that purifies 1309, 218: Science
on prions.
of scrapie and uninfected for
J.
prion brain.
prion
of
proteinNature
replication.
Nature 314: 15, 1985. nature
prions.
retroviruses.
with 1982.
of reverse translation 88: 757, 1981.
on the
puzzling
and
is a sialoglycoprotein.
A mechanism
of
scrapie
agent.
Nature 315: 225, 1985. Cell
32: 5, 1983.
RE.,
Todaro GJ. Evolution of C-type of exogenously acquired viral genes.
142
cause
agent is virus-like in size Nature 308: 658, 1984.
PrP 27-30
Focusing
particles
pathogens.
gene encodes
Scrapie infectious to inactivation.
Persistently R.
novel
infectious
origin
and nature
viral genes: Nature 252: of viruses.
20:
139-142,1986
FROM PRIONS TO PFtIONIC VIRUSES C.I. Sandea. Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322, U.S.A. ABSTRACT The pathogens causing scrapie and other similar degenerative neurological diseases are called “prions” and classified either as It is argued viruses or, more often, as a novel class of pathogens. herein that prions are not the pathogens producing these diseases. The pathogens involved are endogencus viral systems inherited by the host. These endogenous parasites, tentatively named prionic viruses, The prions produce the prions which are horizontally transmitted. trigger the pathological manifestation of prionic viruses. INTRODUCTION The
pathogens causing slow degenerative neurological diseases like scrapie, kuru, and Creutzfeldt-Jacob disease have been designated with meaning proteinaceous particles, which is used, the term “prions”, however, without pre judgement of their physical composition ( 1,2,3).
The
numerous theories concerning the nature of these pathogens have been narrowed in the last few years to two main concepts: 1) prions are viruses (4), or 2) they are a new type of pathogens consisting mainly of protein and devoid of a nucleic acid encoding this protein (1,2,3).
Recent studies indicate that purified preparations of scrapie pathogen consist of a major sialoglycoprotein (PrP 27-30) which seems to be free of nucleic acid (5,6). The unorthodox view that prions may replicate by a protein-directed protein synthesis (7) was refuted very recently, and as expected, a “cellular gene" was shown to encode scrapie PrP 27-30 (3,8). PrP-related nRNA sequences were found at the same levels in uninfected and scrapie infected brains, and at lower levels in other tissues, suggesting that PrP 27-30, or mOre likely a related protein (PrP), is a regular cellular constituent. PrP may be converted to PsP 27-30 by a mechanism in which PrP 27-30 acts as a proteolytic enzyme regenerating itself from PrP (9). Alternatively, there may be some modifications at the genetic level (i.e. PrP DNA sequence, or its ffRNA), that are triggered directly or indirectly by the PrP 27-30, leading eventually to the production of PrP 27-30 (10,111. 139
Doubtless, underlying the nature degenerative
new experiments will soon clarify the molecular mechanism the production of PrP 27-30, but this does not mean that of the pathogens causing scrapie and the other similar neurological diseases will be also revealed (11,~). THE HYPOTHESIS
It
is’hypothesized herein that the prions defined as "small proteinaceous infectious particles which are resistant to inactivation by most procedures that modify nucleic acids” (l), are not the pathogens producing these diseases. They are phenotypic components of some endogenous viruses which are the real pathogens. These phenotypic components are transmitted horizontally triggering the parasitic manifestation of the endogenous viral organisms. The recent findings that PrP 27-30 is encoded by a DNA sequence located within the cells (this by no means qualifies it as a “cellular horizontally (predominantly gene ” 1, and that the system transmitted PrP 27-30) does not contain a nucleic acid are direct evidence supporting the above hypothesis. There is, however, a very appealing conceptual reasoning, extrapolated from what we know about the endogenous viral systems, that recommends this hypothesis even more strongly. In the following model, the nature of scrapie and of other similar pathogens is anticipated by hypothesizing their phylogenetic origin. The model shows why the nature of these pathogens is so difficult to establish, it answers reasonably some of the very prominent questions concerning their genetic features (ll), such as strain diversity and their “adaptation upon fundamentally, nothing is unorthodox about passage 11, it shows that, these pathogens, and finally it is fully testable and very simple. The cells of higher animals, and probably of most organisms, are hosts They are vertically transmitted for numerous endogenous viruses (13). vertical phylogenetic transmission), from parents to offspring (i.e. and evidently from mther cells to daughter cells during the ontogeny of multicellular organisms (i.e. vertical ontogenetic transmission). It is estimated, for example, that as much as 0.3% of the total mouse genome is represented by multiple retrovirus-related sequences (13). Their acquisition rate can be as high as one sequence per 30 gsnerations 4), and they may persist phylogenetically for many millions of RD-114, a cat endogenous virus, probably entered the cat Y ~~~rfi51i~eg~one 5-10 million years ago (15il . Occasionally, some of the endogenous viruses develop vegetatively toward the formation of their reproductive and survival systems (i.e. may infect new host cells (i.e. horizontal virions) f 16)) that transmission). Some other endogenous viruses lost their capability to form virions, thus being limited only to vertical transmission. They may express some of their genetic information in certain host cells, directing the synthesis of phenotypic components whose function is yet to be revealed (13), or their life cycle is reduced to replicative cycles of their DNA. (It should be noted, however, that technically, the DNA molecule is itself a phenotypic component of an organism, 140
This last encoding its genetic information). viruses might be defective or be under repressive the host. Consider
that
an endogenous
virus
forms “defective
group of endogenous control exerted by virions”
which do
not include the viral genome (this is a common feature of many viruses). These “defective virions” might enter a new host cell (also a common feature of many viruses), hosting parental endogenous virus, The result is more where they trigger the activation of this virus. with the potential of activating new endogenous “defective particles” Through such a phenotypic component, having horizontal viruses. controls its own pathogenic accessibility, an endogenous virus This phenotypic expression which otherwise is under host control. component might be something as simple as a single protein. It would be erroneous to consider this viral phenotypic component as being the The pathogen is within cells and through its pathological pathogen. expression the disease is produced. Therefore, if no endogenous virus is present in a cell, administration of prions would not result in the production of new prions leading to degenerative disease. CONCLUSIONS The present model may explain the phylogenetic origins and the nature of the scrapie neurological degenerative pathogens. and other Accordingly, they are endogenous viruses (we may call them ” prionic viruses”) whose horizontally transmitted phenotypic component is named prion. Therefore, the attempts to classify the prions either as viruses or a “novel class of pathogens” are misleading. Physically, biochemically, and conceptually the prions and the prionic viruses are two different entities: the “prionic viruses” are viruses, the prions are phenotypic components of those viruses. By analogy, a bacterium is considered the pathogen and not the bacterial toxin. It is difficult to understand the nature of these pathogens by identifying them with the prions, but much easier when the prionic virus is considered. For example, the prions made by a certain prionic virus might trigger the expression within the same organism of other prionic viruses, having different pathological characteristics and making strain specific prions. The result will be a population of different prions. If these prions are passaged repeatedly in the sane host species, one of the prionic virus strains might be predominantly activated such that the prion population becomes soon homogeneous. This gives the false impression that the prions adapt upon passage (2). In a similar way we may explain the observation that scrapie prions when passaged in mink maintained their ability to induce disease in goats but lost the ability to do so in mice (2). The prions produced after repeated passage in mink were different from those that were initially used; a mink specific prionic virus was predominantly activated producing prions that could further activate a goat prionic virus strain but not a mice prionic virus strain. the model presented herein explains the nature of In conclusion, pathogens producing scrapie and other similar degenerative neurological diseases, and possibly some non-neurological diseases. 141
ACKNOWLEDGMENTS I thank J. manuscript.
Railey
for
and Grace
suggestions,
Vrell
for
typing
the
REFERENCES SB. Novel proteinaceous Science 216: 136, 1982.
1.
Prusiner scrapie.
2.
Prusiner SB. 29: 1, 1984.
3.
Oesch B. et al. A cellular tein. Cell 50% 735, 1985.
4.
Rohwer RG. susceptibility
5.
Bolton the
DC. et al. scrapie
6.
Bolton Virol.
DC. et al. Scrapie 53: 596, 1985.
7.
Craig R. The theoretical possibility proteins into genes. J. Theor. Biol.
8.
Identification Chesebro B. et al. specific mRNAin scrapie-infected 315: 331, 1985.
9.
Brunory Nature.
M., Talbot B. 314: 676, 1985.
10.
Masters
C.
11.
Robertson HD. et al. 40: 725, 1983. Cell.
12.
Harris
13.
Jaenisch
14.
Quint W. et al. Mobility of endogenous ecotropic murine leukemia viral genomes within mouse chromosomal DNA and integration of a mink cell locus-forming virus-type recombinant provirus in the J.Virol. 418 901, 1982. germ line.
15.
Benveniste inheritance 456, 1974.
16.
A new theory on the Bandea CI. J. Theor. Biol. 105: 591, 1983.
T.
Prions:
infectious
Identification prion.
Perspectives
Endogenous
scrapie
Adv. Virus Res. PrP 27-30 pro-
of a protein that purifies 1309, 218: Science
on prions.
of scrapie and uninfected for
J.
prion brain.
prion
of
proteinNature
replication.
Nature 314: 15, 1985. nature
prions.
retroviruses.
with 1982.
of reverse translation 88: 757, 1981.
on the
puzzling
and
is a sialoglycoprotein.
A mechanism
of
scrapie
agent.
Nature 315: 225, 1985. Cell
32: 5, 1983.
RE.,
Todaro GJ. Evolution of C-type of exogenously acquired viral genes.
142
cause
agent is virus-like in size Nature 308: 658, 1984.
PrP 27-30
Focusing
particles
pathogens.
gene encodes
Scrapie infectious to inactivation.
Persistently R.
novel
infectious
origin
and nature
viral genes: Nature 252: of viruses.