| Illustration by Katie O’Leary
n the Australian island of Tasmania around
20 years ago, a disfiguring, fatal cancer of the face was reported to be
rapidly spreading among Tasmanian devils. The disease, known as devil
facial-tumor disease, happens to be an extraordinary instance of infectious
cancer. It is caused not by a virus but by the direct transfer of cancer cells
from one devil to another, possibly through biting.
And it is not unique to devils; other examples of
unusual infectious cancers have been described in species such as dogs
curious cases reveal that some cancer cells can “infect” receptive hosts, but
they by no means indicate that all malignancies should be treated as infectious
diseases. The great majority of cancers arise within the body of the host when
normal cells transform and proliferate uncontrollably. Infectious cancers do, however, highlight the impartial
resourcefulness of biology in both health and disease.
now believe that many of the neurodegenerative diseases that increasingly
plague modern humans bear an intriguing similarity to cancer, except that the
disease agents that proliferate in these brain disorders are not transformed
cells, but rather transformed proteins that have folded into the wrong shape.
Such “malignant” proteins are key players in such devastating diseases as
Alzheimer’s, Parkinson’s, Huntington’s, frontotemporal dementia, chronic
traumatic encephalopathy (CTE), amyotrophic lateral sclerosis (ALS), and Creutzfeldt-Jakob
disease (CJD). Most of these maladies are thought to be non-contagious under
ordinary circumstances, but CJD and its variants have been transmitted to
humans by tainted meat, cannibalism, and tissue transplants, and research
suggests that other disease-linked malignant proteins can in some circumstances
transmit their properties from one organism to another.
in the case of cancerous cells, though, these rogue proteins almost always emerge
and propagate within the affected host. Once the misfolded proteins gain a
foothold in the nervous system, they effectively compel normal versions of the
same protein to adopt the same malformed state. In this faulty configuration,
the proteins stick to one another and, in a molecular chain-reaction,
structurally corrupt like molecules that are generated in the course of normal
cellular metabolism. In many instances, the final products of this process are
clumps of the protein called amyloid (Figure 1). Central to this process is what
we call seeded protein aggregation (seeding for short), a surprisingly common disease
mechanism that first came to light with the discovery that protein seeds called
prions can act as infectious agents.
The steps leading from a
single protein molecule to clumps of amyloid. The misfolded proteins act as
seeds that accelerate the crystallization-like disease process. The seeds can
vary in size, and very small assemblies called oligomers can be particularly
toxic to cells. In prion diseases, the
seeds can sometimes be transferred from one organism to another (“infection”).
Image courtesy of Lary Walker/Mathias Jucker
The Prevailing Prion
The improbable tale of infectious proteins
began in the 1730s, when reports of a slowly progressing and ultimately fatal
disease of sheep first appeared in the European scientific literature. British
farmers called the disease scrapie because affected sheep were seen to scrape
the wool from their skin by compulsively rubbing against farmyard objects. The
farmers suspected even then that scrapie was contagious, but it wasn’t until
the 1930s that transmission of the disease was demonstrated experimentally by Jean Cuillé and Paul-Louis Chelle in
To establish infectivity, Cuillé and Chelle injected homogenized
nervous tissue from scrapie-afflicted donor sheep into healthy host sheep. Infectious
illnesses usually emerge within days or weeks, but earlier experiments had
failed to demonstrate transmission of scrapie in this timeframe. Cuillé and Chelle, however, were
patient; the sheep that they injected with scrapie-tainted tissue finally
succumbed to the disease more than a year later.
Thus began a long and prickly debate about
the nature of the scrapie agent: What kind of infectious pathogen causes
disease only after months or years of incubation? Furthermore, infections
usually announce their presence with inflammation and fever, yet scrapie showed
no such signs. The term “slow virus” was adopted by many, but evidence
gradually mounted that the culprit was not a virus at all, but rather, just
possibly, an infectious protein.
Interest in the problem intensified in the
1960s when D. Carleton Gajdusek and his colleagues made the Nobel Prize-winning
discovery that, like scrapie, two rare human neurodegenerative diseases, kuru
and Creutzfeldt-Jakob disease, are transmissible with very long incubation
By then it was becoming clear that the agent of infection was strange
indeed. Radiobiological experiments performed by Tikvah Alper strongly
suggested that the agent did not require nucleic acids to replicate,
and the mathematician John
Griffith described, prophetically, how a protein-only agent might multiply
using the host’s genetic machinery to generate more protein.
In 1982, Stanley Prusiner crystallized
the protein-only concept (and enraged its opponents
) by naming the scrapie agent a “proteinaceous
infectious particle,” or “prion.” In subsequent years, Prusiner’s group, along
with a growing cadre of allies, amassed persuasive experimental support for the
prion concept, for which Prusiner was awarded the Nobel Prize in 1997. Although
echoes of the old debate about the causative agent still sometimes find their
way into print,
the prion paradigm has prevailed,
and today is evolving into a far-reaching new concept of disease.
Assembling Into Amyloid
The prions of CJD and scrapie are
submicroscopic assemblies of a natural mammalian protein known as prion
protein, or PrP. Prions consist of misfolded versions of PrP that can seed the
formation of similar assemblies by a process resembling the seeded
crystallization seen in some chemical reactions
). In this
sense, PrP prions can be viewed as malignant proteins that multiply and spread
within the nervous system, eventually causing neurological dysfunction and
death. In humans, PrP prions trigger progressive, fatal neurodegenerative
disorders that include CJD, kuru, Gerstmann-Sträussler-Scheinker disease, and
In nonhuman species, the PrP prion
diseases include scrapie, bovine spongiform encephalopathy (“mad cow disease”),
and chronic wasting disease (CWD) of North American deer, elk, and moose.
Figure 2: Spongiform vacuoles (here
seen in the microscope as holes) in a thin slice of the brain of a patient who
died of Creutzfeldt-Jakob disease, a prion disease. Neurons and the nuclei of
other brain cells are darkly stained.
Image courtesy of
Lary Walker/Mathias Jucker
Before the discovery of prions, these diseases often were called spongiform encephalopathies due to the appearance of sponge-like vacuoles in the brain (Figure 2). Despite being caused by just one type of protein—PrP—different prion diseases display remarkably different clinical and pathological signs, and these differences appear to be related to distinct molecular features of the prions.18 The exact mechanisms by which nervous tissues are damaged in prion diseases (and other neurodegenerative disorders) remain incompletely understood—and that poses a pressing challenge for future research.
The enigma of infectious proteins was
deepened with the discovery that PrP prion diseases also can be caused by
mutations in the gene that encodes PrP.9,12 These
hereditary forms of prion disease, ironically, helped to establish the
protein-only hypothesis of the infectious agent, as they confirmed the
importance of normally generated PrP in the creation of new prions. In other
words, hereditary (and presumably also spontaneous) PrP prion disease begins
when prions are formed by the misfolding of PrP that is generated by cells inside
the body. Infectious prion disease, in contrast, results when external prions
invade the body of the host. But in all cases, once the process begins, the
abnormal prion protein accumulates in the nervous system and triggers the
impairment and death of neurons. As abnormal PrP aggregates build up in the
brain, they sometimes clump into distinctive masses of amyloid.18
This attribute of misfolded
PrP—its ability to assemble into amyloid—furnishes telling clues to the nature
of the prion. Surprisingly, amyloid-forming proteins also characterize more
common age-related neurodegenerative diseases, such as Alzheimer’s disease. While
amyloid is obvious under the light microscope (see Figure 1), the amyloid
itself may only be the tip of the iceberg; the aberrant proteins often form
assemblies that are not amyloid in the strict sense of the word, and in many
instances, much smaller clusters of misfolded protein molecules called
oligomers have been found to be quite toxic to cells.
: The pathological face of
Alzheimer’s disease: In a slice of the brain of an Alzheimer patient viewed at
high magnification, three spherical clumps of Aβ form senile (Aβ) plaques, and
aggregated tau forms flame-shaped neurofibrillary (tau) tangles in surrounding
Image courtesy of
Lary Walker/Mathias Jucker
Other Plaques and Tangles
Intriguing similarities, such as the presence of amyloid and relentless decline of brain function, suggested to Gajdusek, Prusiner, and others that the prion diseases might yield insights into the cause of Alzheimer’s, Parkinson’s, and other human neurodegenerative disorders. Virtually all of these maladies involve the appearance of characteristic protein deposits in the brain. For example, in Alzheimer’s disease (the most frequent cause of dementia), a protein called amyloid beta (Aβ) aggregates to create the “senile plaque” formations seen in the gray matter of all Alzheimer’s brains (Figure 3), as well as cerebral amyloid angiopathy, a buildup of amyloid in the walls of brain blood vessels. Another protein called tau also can adopt the amyloid structure, forming neurofibrillary tangles in Alzheimer’s (Figure 3). While both plaques and tangles are necessary to drive Alzheimer’s disease, the prime mover in the degenerative cascade appears to be Aβ.19 In Parkinson’s disease, yet another protein known as α-synuclein assembles into intracellular amyloid clumps called Lewy bodies. The list of diseases and their misshapen proteins continues to grow.11 In each disease, the flawed proteins are associated with distinctive signs and symptoms. But are they, like PrP prion disease, transmissible?
In the 1960s, Gajdusek’s group began a
massive study to address this very question. Specifically, they wanted to know
if non-PrP neurodegenerative diseases such as Alzheimer’s are transmissible to
nonhuman primates? The outcome was essentially negative.20 In Great Britain, however, a
team led by Rosalind Ridley and Harry Baker reported in the early 1990s that Aβ
plaques and cerebral amyloid angiopathy are increased in the brains of marmosets
several years after injection of Alzheimer brain homogenates into the brain.21 The actual agent that
precipitated these amyloid deposits, however, remained uncertain.
These researchers logically used nonhuman
primates to assess the potential transmissibility of Alzheimer’s disease, since
close evolutionary relatives are most likely to manifest the same type of
disease. Such experiments, however, were hampered by issues of time and cost.
Normal laboratory mice and rats were not suitable for these experiments because
the chain of amino acids that makes up rodent Aβ differs from that in humans
and monkeys; for that and perhaps other reasons, rats and mice do not naturally
develop amyloid deposits in the brain as they grow old. In the mid-1990s,
however, genetically engineered mouse models were introduced that make
human-sequence Aβ. These “transgenic” mice generate amyloid plaques within a
matter of months, and thus were widely adopted as the first practical animal
models for studying Alzheimer-like Aβ aggregation in the brain.
With this important new tool in hand, the two
of us set out to test the hypothesis that Aβ-amyloid can be induced to form in
the brains of transgenic mice by a mechanism similar to the infectivity of PrP prions.
In our earliest studies, we homogenized brain tissue from Alzheimer patients,
spun it briefly in a centrifuge to remove larger debris, and injected a small
amount (usually one to four millionths of a liter, or microliters) of the clear
extract into the brains of transgenic mice expressing human-sequence Aβ. After
an incubation period of several months, the mice began to develop Aβ plaques
and cerebral amyloid angiopathy in the injected region, similar in many ways to
the Aβ amyloid pathology seen in Alzheimer’s. Subsequent experiments in our
labs and others have shown that the seeding agent is indeed aggregated Aβ.
The mice did not develop full-blown
Alzheimer’s disease, which, to the best of our current knowledge, occurs only
in humans. Research has shown, however, that at the molecular level, Aβ seeds
resemble PrP prions in virtually every way: they consist solely of a particular
protein; the seeds vary in size; they resist destruction by high temperature or
formaldehyde; they can spread within the brain and to the brain from elsewhere
in the body; and different seed structures have different biological properties
(variants that are referred to as strains).
More recently, numerous elegant studies have
found that proteins involved in other neurodegenerative diseases also have
prion-like properties. These proteins include tau (which forms neurofibrillary
tangles in Alzheimer’s disease, CTE, and many other disorders), α-synuclein
(which forms Lewy bodies in Parkinson’s disease, Lewy body dementia, and
multiple system atrophy), huntingtin (which forms inclusion bodies in
Huntington’s disease), and several proteins with prion-like properties that
accumulate in such disorders as ALS and frontotemporal dementia.
A growing awareness of the similarities
between PrP prions and other protein seeds has revived speculation that
Alzheimer’s and other neurodegenerative diseases might be infectious. This
question gained recent prominence with a report from a team led by Sebastian
Brandner and John Collinge in Great Britain showing that at least one facet of
Alzheimer’s disease—Aβ-amyloid formation—appeared to be induced in patients who
were treated as children with human growth hormone in order to correct short
discovered in the mid-1980s that some of the growth hormone used for treatment,
which had been isolated from large batches of human pituitary glands collected
at autopsy, was contaminated with PrP prions. As a result, some recipients died
of Creutzfeldt-Jakob disease many years after their growth hormone treatments
had ceased. Brandner, Collinge, and co-workers were able to examine the brains
of eight of them who were 36- to 51-years-old at the time of death. In addition
to PrP prion pathology, four of the patients also had substantial Aβ accumulation
in plaques and cerebral blood vessels, and two others had sparse Aβ deposits.
The appearance of Aβ plaques and vascular
amyloid in people at such a young age is quite unusual. The findings strongly
suggest that some batches of growth hormone were contaminated with Aβ seeds in
pituitary glands that were inadvertently collected from Alzheimer patients.
Remarkably, none of the eight subjects had evidence of neurofibrillary tangles,
the other defining brain abnormality in Alzheimer’s disease. Because all of
them had died of prion disease, we cannot know whether they eventually would
have developed Alzheimer’s. If so, the incubation period would likely be at
least as long as that of prion disease.
This presumed transmission of Aβ-amyloidosis
to humans occurred under extraordinary circumstances—repeated, long-term
injections of a hormone derived from pooled human pituitary glands. By sheer
good luck, recombinant growth hormone (produced by genetically modified
bacteria) became available in 1985, just at the time when the cadaver-derived
hormone was confirmed to be contaminated with PrP prions. The recipients were
quickly switched to this safer version of the agent. Strangely (or perhaps
not), a black market continued to flourish for cadaver-derived growth hormone,
sustained in large part by body-builders and other athletes; the
cadaver-derived hormone is indistinguishable from that produced by the
recipient, and thus is difficult to detect in doping tests.
Fortunately, most of the patients treated
with growth hormone prior to 1985 have not developed prion disease. It will be
important to follow them in the coming years to determine whether they are at
higher risk of Alzheimer’s disease and other neurodegenerative disorders
involving protein seeds. Interestingly, a team of Swiss and Austrian
researchers recently reported a similar induction of Aβ deposition in CJD patients
many years after they had received transplants of PrP prion-contaminated dura
mater that had been harvested from human cadavers.
These studies by no means
indicate that Alzheimer’s disease can be transmitted from person-to-person
under everyday circumstances; rather, they do
provide the first evidence that the aggregation of a protein other than PrP
might be induced in the human brain by exogenous seeds. Just as cancer cells
can occasionally transmit disease from one animal to another, the same appears
to be true—under exceptional circumstances—for some pathogenic protein seeds.
Promise and Pitfalls
of the Prion Paradigm
In Alzheimer’s and other non-PrP neurodegenerative
diseases, malignant protein seeds arise from normally generated proteins inside
the body, just as malignant cells stem from normal cells in cancer. Nature also
has exploited the prion mechanism for beneficial ends; proteins that form
prion-like aggregates handle functions ranging from information transfer in
storage of peptides
consolidation of memory
In light of these discoveries, we have argued that the term “prion” should be
re-defined as a “proteinaceous nucleating particle” to stress the molecular
process of seeded protein aggregation (nucleation) that is common to all of
By removing the disquieting word
“infectious,” the new definition accommodates the many instances in which such
proteins are not infectious by any customary definition of the term.
has brought into clearer focus the devastating role of malignant proteins in
Infectivity is undoubtedly an important characteristic of PrP prions,
particularly in some nonhuman species. Chronic wasting disease, for example, is
rapidly spreading among members of the deer family in western North America.
In humans, though, most cases of
PrP prion disease do not result from infection.
prions achieved notoriety largely due to their infectivity, this peculiar
feature has colored our view of all cases of PrP prion disease, whether they
are caused by infection or not. In light of the history of the prion concept,
one has to wonder how we would view cancer if the first malignancy discovered
had been devil facial-tumor disease, and only later did we learn that most
cancerous cells actually develop within the body of the affected organism.
Would we now consider all cancers to be potentially infectious? And at what
cost to the patients and those who care for them? Our perception of disease,
and the language we use to define it, must continually adapt to new
information. By highlighting the molecular properties of malignant proteins,
the evolving prion concept will help to guide future experimental strategies
for defeating a multitude of intractable conditions.
: The authors
have no conflicts of interest to report.
1 Bender, H. S., Marshall Graves, J. A. & Deakin, J.
E. Pathogenesis and molecular biology of a transmissible tumor in the Tasmanian
devil. Annu Rev Anim Biosci2, 165-187,
2 Strakova, A. & Murchison, E.
P. The cancer which survived: insights from the genome of an 11000 year-old
cancer. Curr Opin Genet Dev30, 49-55,
3 Metzger, M. J., Reinisch, C.,
Sherry, J. & Goff, S. P. Horizontal transmission of clonal cancer cells
causes leukemia in soft-shell clams. Cell161, 255-263,
4 Schwartz, M. How the Cows Turned Mad.
(University of California Press, 2003).
5 Cuille, J. & Chelle, P.-L. La
maladie dite tremblante du mouton est-elle inoculable? Comptes Rendus de l'Academie des Sciences203, 1552-1554 (1936).
6 Gajdusek, D. C. Unconventional
viruses and the origin and disappearance of kuru. Science197, 943-960
7 Alper, T., Cramp, W. A., Haig, D.
A. & Clarke, M. C. Does the agent of scrapie replicate without nucleic
acid? Nature214, 764-766 (1967).
8 Griffith, J. S. Self-replication
and scrapie. Nature215, 1043-1044 (1967).
9 Prusiner, S. B. Madness and Memory. (Yale University Press, 2014).
10 Couzin-Frankel, J. Scientific
community. The prion heretic. Science332, 1024-1027,
11 Jucker, M. & Walker, L. C.
Self-propagation of pathogenic protein aggregates in neurodegenerative
diseases. Nature501, 45-51, doi:10.1038/nature12481 (2013).
12 Prusiner, S. B. Biology and genetics
of prions causing neurodegeneration. Annu
Rev Genet47, 601-623,
13 Walker, L. C. & Jucker, M. Seeds
of dementia. Sci Am308, 52-57 (2013).
14 Walker, L. C. & Jucker, M.
Neurodegenerative diseases: expanding the prion concept. Annu Rev Neurosci38,
87-103, doi:10.1146/annurev-neuro-071714-033828 (2015).
15 Lansbury, P. T., Jr. & Caughey,
B. The chemistry of scrapie infection: implications of the 'ice 9' metaphor. Chem Biol2, 1-5 (1995).
16 Imran, M. & Mahmood, S. An
overview of human prion diseases. Virology
17 Imran, M. & Mahmood, S. An
overview of animal prion diseases. Virology
journal8, 493, doi:10.1186/1743-422X-8-493
18 DeArmond, S. J., Ironside, J. W.,
Bouzamondo-Bernstein, E., Peretz, D. & Fraser, J. R. in Prion Biology and Diseases (ed S. B. Prusiner) 777-856 (Cold Spring Harbor Laboratory Press,
19 Hardy, J. & Selkoe, D. J. The amyloid
hypothesis of Alzheimer's disease: progress and problems on the road to
therapeutics. Science297, 353-356,
doi:10.1126/science.1072994 297/5580/353 [pii] (2002).
20 Goudsmit, J. et al. Evidence for and against the transmissibility of Alzheimer
disease. Neurology30, 945-950 (1980).
21 Baker, H. F., Ridley, R. M., Duchen,
L. W., Crow, T. J. & Bruton, C. J. Induction of beta (A4)-amyloid in
primates by injection of Alzheimer's disease brain homogenate. Comparison with
transmission of spongiform encephalopathy. Mol
Neurobiol8, 25-39 (1994).
22 Brettschneider, J., Del Tredici, K.,
Lee, V. M. & Trojanowski, J. Q. Spreading of pathology in neurodegenerative
diseases: a focus on human studies. Nat
Rev Neurosci16, 109-120,
23 Goedert, M. NEURODEGENERATION.
Alzheimer's and Parkinson's diseases: The prion concept in relation to
assembled Abeta, tau, and alpha-synuclein. Science349, 1255555,
24 King, O. D., Gitler, A. D. &
Shorter, J. The tip of the iceberg: RNA-binding proteins with prion-like
domains in neurodegenerative disease. Brain
25 Ayers, J. I., Fromholt, S. E.,
O'Neal, V. M., Diamond, J. H. & Borchelt, D. R. Prion-like propagation of
mutant SOD1 misfolding and motor neuron disease spread along neuroanatomical
pathways. Acta Neuropathol,
26 Jaunmuktane, Z. et al. Evidence for human transmission of amyloid-beta pathology
and cerebral amyloid angiopathy. Nature525, 247-250,
27 Holt, R. I. & Sonksen, P. H.
Growth hormone, IGF-I and insulin and their abuse in sport. Br J Pharmacol154, 542-556, doi:10.1038/bjp.2008.99 (2008).
28 Frontzek, K., Lutz, M. I., Aguzzi,
A., Kovacs, G. G. & Budka, H. Amyloid-beta pathology and cerebral amyloid
angiopathy are frequent in iatrogenic Creutzfeldt-Jakob disease after dural
grafting. Swiss Med Wkly146, w14287, doi:10.4414/smw.2016.14287
29 Wickner, R. B. et al. Yeast prions: structure, biology, and prion-handling
systems. Microbiol Mol Biol Rev79, 1-17, doi:10.1128/MMBR.00041-14
30 Maji, S. K. et al. Functional amyloids as natural storage of peptide hormones
in pituitary secretory granules. Science325, 328-332,
31 Fioriti, L. et al. The Persistence of Hippocampal-Based Memory Requires
Protein Synthesis Mediated by the Prion-like Protein CPEB3. Neuron86, 1433-1448, doi:10.1016/j.neuron.2015.05.021 (2015).
32 Haley, N. J. & Hoover, E. A.
Chronic wasting disease of cervids: current knowledge and future perspectives. Annu Rev Anim Biosci3, 305-325,