SEMINAR ON "PRION DISEASES; HOW SAFE ARE WE IN AFRICA?"

1. PRION DISEASES:
HOW SAFE ARE WE
IN AFRICA?
P L A T E A U S T A T E U N I V E R S I T Y ,
B O K K O S
F A C U L T Y O F N A T U R A L A N D
A P P L I E D S C I E N C E S
D E P A R T M E N T O F B I O C H E M I S T R Y
BENSON, MATTHEW LASSA
PLASU/2013/FNS/0025

2. PRION DISEASES: HOW SAFE ARE WE IN AFRICA?
BY
BENSON MATTHEW LASSA
PLASU/2013/FNS/0025
SUBMITTED TO THE DEPARTMENT OF BIOCHEMISTRY
SCHOOL OF NATURAL AND APPLIED SCIENCES,
PLATEAU STATE UNIVERSITY, BOKKOS
BOKKOS, PLATEAU STATE
IN PARTIAL FULFILMENT FOR THE AWARD OF
BACHELOR OF SCIENCE (B.Sc.) IN BIOCHEMISTRY
MAY, 2017

3. CERTIFICATION
BENSON MATTHEW LASSA, an undergraduate student with Matriculation Number
PLASU/FNS/0025 in the Department of Biochemistry has satisfactorily completed the seminar
in biochemistry literature review under the supervision of Prof. MATHEW C. OKAFOR.
___________________ ____________________
Prof. M. C. OKAFOR DR. F. O. OKONKWO
(Supervisor) (Head of Department)

4. DEDICATION
This tedious work is dedicated to God Almighty for the grace to attempt making a great review
of literature.

5. ACKNOWLEDGEMENT
I genuinely appreciate my parents, Mr. & Mrs. Benson Lassa, for their persisting patience, love
and financial support. My sincere gratitude to the friends who became family: Sheku, RS
Michael, CN and Tungon, RI for helping me source for journals and for being of help always. I
also appreciate my brothers for the tough time they gave which pushed me to work harder, Joel
and Destiny.
My sincere gratitude goes to my supervisor Prof. Mathew C.O. whose meticulous guidance and
direction has seen me thus far.
My gratitude also goes to all lecturers and members of staff of the Biochemistry department,
Plateau State University, Bokkos.

6. TABLE OF CONTENT
Title Page -------------------------------------------------------------------------------------------------------i
Certification ---------------------------------------------------------------------------------------------------ii
Dedication ----------------------------------------------------------------------------------------------------iii
Acknowledgement -------------------------------------------------------------------------------------------iv
Table of Content ----------------------------------------------------------------------------------------------v
Abstract -------------------------------------------------------------------------------------------------------vii
Abbreviation ------------------------------------------------------------------------------------------------viii
CHAPTER ONE
1.0 Introduction -----------------------------------------------------------------------------------------------1
CHAPTER TWO
2.0 Review of Related Literature----------------------------------------------------------------------------3
2.1 Introduction -----------------------------------------------------------------------------------------------3
2.2 Human prion diseases------------------------------------------------------------------------------------3
2.2.1 Creutzfeldt-Jakob disease (CJD) ---------------------------------------------------------------------3
2.2.2 Sporadic CJD -------------------------------------------------------------------------------------------4
2.2.3 Familial CJD --------------------------------------------------------------------------------------------5
2.2.4 Iatrogenic CJD -----------------------------------------------------------------------------------------6
2.2.5 Variant CJD ---------------------------------------------------------------------------------------------7

7. 2.2.6 Kuru -----------------------------------------------------------------------------------------------------7
2.2.7 Gertsmann-straussler-scheinker syndrome (GSS) -------------------------------------------------8
2.3 Animal prion diseases -----------------------------------------------------------------------------------8
2.3.1 Scrapie of sheep ----------------------------------------------------------------------------------------8
2.3.2 Transmissible mink encephalopathy (TME) -------------------------------------------------------9
2.3.3 Chronic wasting disease of cervids ----------------------------------------------------------------10
2.3.4 Bovine spongiform encephalopathy ---------------------------------------------------------------10
2.4 Risk assessment -----------------------------------------------------------------------------------------11
2.5 Natural transmission -----------------------------------------------------------------------------------11
2.6 Species barriers -----------------------------------------------------------------------------------------12
2.7 The concept of prion strains ---------------------------------------------------------------------------13
2.8 Molecular Mechanisms of Prion Disease Pathogenesis -------------------------------------------14
CHAPTER THREE
3.0 Conclusion -----------------------------------------------------------------------------------------------15
References ----------------------------------------------------------------------------------------------------16

8. ABSTRACT
Prion diseases are transmissible, progressive and invariably fatal neurodegenerative
conditions affecting animals and humans alike associated with misfolding and aggregation of
a host-encoded cellular prion protein, PrPC. Human prion diseases include Creutzfeldt–Jakob
desease (CJD), Gerstmann-Straussler–Scheinker disease (GSS), Kuru, and fatal familial
insomnia (FFI). These diseases are caused by transmissible particles that contain a
pathogenic isoform of the prion protein, a normal constituent of cell membranes. They may be
sporadic, infectious, or inherited in origin. Sporadic human prion diseases include
Cruetzfeldt-Jacob disease (CJD), fatal insomnia and variably proteasesensitive prionopathy.
Genetic or familial prion diseases are caused by autosomal dominantly inherited mutations in
the gene encoding for PrPC and include familial or genetic CJD, fatal familial insomnia and
Gerstmann-Sträussler-Scheinker syndrome. Acquired human prion diseases account for only
5% of cases of human prion disease. They include kuru, iatrogenic CJD and a new variant
form of CJD that was transmitted to humans from affected cattle via meat consumption
especially brain.

9. ABBREVIATIONS
BSE - Bovine Spongiform Encephalopathy
CJD - Creutzfeldt-Jakob Disease
CNS – Central Nervous System
CSF – Cerebrospinal Fluid
CWD – Chronic wasting disease
DNA – Deoxyribonucleic Acid
fCJD – Familial CJD
FFI - Fatal Familial Insomnia
FSE – Feline Spongiform Encephalopathy
GSS - Gerstmann-Stra¨ussler-Scheinker syndrome
iCJD – Iatrogenic CJD
MBM – Meat and Bone meal
MRI – Magnetic Resonance Imaging
nvCJD – New Variant CJD
Prion – Proteinous Infections
PRNP – Prion Protein Gene
PrP – Prion Protein
PrPSc – Scrapie Prion Protein
RNA – Ribonucleic Acid
sCJD – Sporadic CJD

10. TME – Transmissible Mink Encephalopathy
TSE - Transmissible Spongiform Encephalopathy
UK – United Kingdom
USA – United States of America
vCJD – Variant CJD

11. CHAPTER ONE
1.0 INTRODUCTION
Prion diseases are a group of progressive neurodegenerative conditions (Rudd et al., 1999).
These illnesses exist in both animals and humans. Prion diseases, also called transmissible
spongiform encephalopathies (TSEs), lead to neurological dysfunction in animals and are fatal
(Lee, Kim, Hwang, Ju, & Woo, 2013). These diseases are fatal neurodegenerative disorders that
include scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle, chronic
wasting disease (CWD) in deer and elk, and feline spongiform encephalopathy (FSE), albino
tigers, pumas, and cheetahs (Prusiner, 1997). Creutzfeldt-Jakob disease (CJD), Gerstmann-
Sträussler-Scheinker disease (GSS), fatal familial insomnia (FFI), kuru and most recently variant
CJD (vCJD) in humans (Wadsworth, Hill, Beck, & Collinge, 2003).
The word PRION, derived from ‗proteinaceous infectious particle‘; meaning that the infectious
agent consists only of protein with no nucleic acid genome. Prions are the only known example
of infectious pathogens that are devoid of nucleic acid. All other infectious agents, like bacteria,
viruses, fungi possess genomes composed of either DNA or RNA that direct the synthesis of
their progeny (Kalikiri & Sachan, 2003; Aguzzi & Weissmann, 1996; Ironside, 1998).
Abnormal forms of the prion protein (a ubiquitous protein of unknown function) cause these
neurodegenerative diseases. The disease occurs when the normal cellular prion protein undergoes
a conformational change to the abnormal form. This may occur spontaneously at an extremely
low rate or at a higher rate if there is a defect in the gene. The agent can "replicate" when the
abnormal form crosses the path of the normal, cellular prion protein and the abnormal prion
induces the normal form to adopt a similar abnormal form. Prions accumulate in the brain as an
insoluble complex of proteins called an amyloid (Prusiner, 1995; Nair & Johnson, 2011).
The interaction of prions with the normal cellular prion proteins damages the cell and leads to its
slow degeneration and death. This releases prions, which can then induce more prions on the
surface of surrounding cells, causing more degeneration and death of cells. This process of
spreading cell death accounts for the holes in the brain. The current idea is that other tissues are
not much affected because prion protein is mainly produced in nerve cells. Lymphoid cells also
have a lot of prion protein and they are important in spreading the infection to nerve cells.
However, lymphoid cells are readily replaced, whereas a process that destroys neurones, even a
slowly progressive one, will lead to disease, since nerve cells cannot normally be replaced.

12. Transmissible spongiform encephalopathies are uniformly fatal and often characterized by a long
incubation period and a multifocal neuropathologic picture of neuronal loss, spongiform
changes, and an abnormal increase in the number of astrocytes due to the destruction of nearby
neurons from CNS trauma, infection, ischemia, stroke, autoimmune responses, and
neurodegenerative disease (Huang, Prusiner & Cohen, 1996; Nair & Johnson, 2011).

13. CHAPTER TWO
2.0 REVIEW OF RELATED LITERATURE
2.1 Introduction
Creutzfeldt-Jakob disease (CJD), the most common human prion disease, is a rare form of adult
dementia; the disease was not widely recognized until the 1960s. In the past years, CJD has
become a prominent consideration in the differential diagnosis of chronic neurological diseases.
The growing interest in the disease is not caused by increasing incidence, which is estimated to
be stable at between 0·5 and 1·5 cases per million people per year. This focus on CJD and other
prion diseases stems from basic biological studies on the nature of the transmissible agents,
which have raised fundamental new questions in biochemistry and microbiology, and from the
emergence of bovine spongiform encephalopathy (BSE) in the United Kingdom. The highly
publicized spreads of BSE outside of the UK and the transmission to human beings have had
major economic and political repercussions all over the globe (Africa exclusive) (Johnson &
Gibbs, 1998).
2.2 HUMAN PRION DISEASES
Prions cause different kinds of diseases in humans as the infection can arise in different regions
of the brain. CJD is the commonest human prion disease (Gambetti et al., 2008) and the sporadic
form of CJD accounts for about 85% of cases; about 10–15% of cases are familial, 1%
iatrogenic, and variant CJD is a regional disease limited largely to the UK and France. Kuru was
the first spongiform encephalopathy of human beings to be experimentally transmitted to non-
human primates. This disease is of importance not only for historical reasons but also because of
lessons learned about modes of transmission and incubation periods associated with transmission
among human beings (Johnson, 2005).
2.2.0 Creutzfeldt-Jakob disease (CJD)
Creutzfeldt-Jakob disease (CJD) is a rare, rapidly progressive fatal central nervous system (CNS)
disorder. Two German neurologists, Hans Gerhard Creutzfeldt and Alfons Maria Jakob, first
described Creutzfeldt-Jakob disease. Some of the clinical findings described their first papers do
not match current criteria for CJD, and it is considered highly likely that at least two of the

14. patients in their initial studies were suffering from a different disorder (Obi & Nwanebu, 2008).
CJD is a very rare and incurable degenerative neurological disorder (brain disease) that is
ultimately fatal. It is the most common of the TSEs (Todd et al., 2005). Typically, onset of
symptoms occurs at about age 60. Three major categories of the disease exist. These are the
sporadic, hereditary and acquired CJDs (Obi & Nwanebu, 2008).
The prion that is believed to cause CJD exhibits at least two stable conformations. One, the
native state, is water-soluble and present in healthy cells. As at 2006, its biological function was
unknown. The other conformational state is very poorly water-soluble and readily forms protein
aggregates (Shmakov & Ghosh, 2001). The CJD prion is dangerous because it promotes
refolding of native proteins into the diseased state. Subsequently the number of misfolded protein
molecules will increase exponentially and the process will lead to a large quantity of insoluble
prions in affected cells. This mass of misfolded proteins disrupts cell functions and cause cell
death. Once the prion is transmitted, the defective proteins invade the brain and get produced in a
self-sustaining feedback loop, causing exponential spread of the prion, and the patient usually
dies within a few months although a few patients have been known to live as long as two years
(McDonnell & Burke 2003).
Although CJD is the most common prion human disease, it is still rare and only occurs about one
out of every one Million people. It usually affects people aged 45-75, most commonly appearing
in people between the ages of 60-65. The exception to this is the more recently recognized
"variant" CJD (vCJD), which occurs in younger people (Obi & Nwanebu, 2008). Some cases of
CJD are clustered in certain families, and the fact that some of these families also have an
apparently higher incidence of Alzheimer's disease has led to the supposition that the two
diseases may be related (Obi & Nwanebu, 2008).
2.2.1 Sporadic CJD
Creutzfeldt-Jakob disease consists of three main catalogues: sporadic, familial and iatrogenic
CJD. The reasons of sporadic CJD are still unclear (Prusiner, Telling, Cohen, & DeArmond,
1996). CJD was first described in the early 1920s. The predominant subtype of human prion

15. diseases, sCJD, occurs equally in both sexes with a peak age of onset between 60 and 69 years
(Gao et al., 2011; Ladogana et al., 2005). sCJD occurs all year round, with no seasonal
specificity. Typical clinical symptoms include progressive dementia, accompanied by visual and
cerebellum function abnormalities (Brown et al., 1994). sCJD, caused by the spontaneous
misfolding of prion-protein in an individual. This accounts for 85% of cases of CJD.
The disease affects men and women equally, average age at onset is 60 years, and it is rare in
people under age 40 years or over age 80 years. The initial symptoms in about a third of cases
are systemic complaints of fatigue, disordered sleep, and decreased appetite; about a third of
patients present with behavioral or cognitive changes; and the final third have focal signs such as
visual loss, cerebellar ataxia, aphasia, or motor deficits. The disease progresses rapidly with
prominent cognitive decline and the development of myoclonus, particularly startlesensitive
myoclonus. The median time to death from onset is only 5 months, and 90% of patients with
sporadic CJD are dead within 1year (Johnson et al., 1998; Brown et al., 1994).
Characteristic patterns on MRI, the synchronized biphasic or triphasic sharp-wave complexes on
the electroencephalogram, and the finding of 14-3-3 protein in CSF all support the diagnosis of
CJD (Tschampa et al., 2005; Steinhoff et al., 2005), but none are 100% sensitive or specific.
MRI and electroencephalogram changes are commonly found only with repeated examination,
and 14-3-3, a normal neural protein released with rapid neuronal loss, is present in CSF after
strokes or during encephalitis. The pathological findings in CJD are limited to the brain and
spinal cord. There is neuronal loss, and vacuolization within cell bodies and dendrites that gives
a spongiform appearance to the cortex and deep nuclei. The pathogenic isoform of prion protein
can be demonstrated in brain by immunocytochemical staining and by western-blot analysis.
The mode of infection is unknown. Exposure to people with the illness, even the intimate
exposure of years of marriage, does not seem to increase the risk, and there has been only one
documented conjugal case pair (Brown et al., 1998).
2.2.2 Familial CJD
Familial CJD, (fCJD), caused by an inherited mutation in the prion-protein gene (Budka & Will,
2015). This accounts for the majority of the other 15% of cases of CJD. Familial CJD cases show
autosomal dominant inheritance of mutations in PRNP. Over 50 different mutations in PRNP

16. have been found in kindred with familial CJD; but four point mutations—at codons 102, 178,
200, and 210—and insertions of five or six octapeptide repeats account for 95% of the familial
cases (Capellari et al., 2005). In addition, a polymorphism (difference) at codon 129 leads to the
protein containing either methionine or valine. This polymorphism influences susceptibility to or
phenotype of CJD (Palmer & Dryden, 1991). For example, over 80% of patients with sporadic
CJD are homozygous at this site compared with 49% of healthy controls (Palmer & Dryden,
1991; Mastrianni, 2005).
In general, familial CJD has earlier age of onset and longer clinical course than sporadic CJD.
The commonest familial form of CJD results from mutation at codon 200, and the phenotype in
patients with this mutation resembles that of sporadic CJD (Mastrianni, 2005). Several other
mutations result in a phenotype sufficiently different from sporadic CJD that distinct names have
been used.
2.2.3 Iatrogenic CJD
Iatrogenic CJD is caused by contamination with tissue from an infected person, usually as the
result of a medical procedure. Medical procedures that are associated with the spread of this form
of CJD include blood transfusion from the infected person, use of human-derived pituitary
growth hormones, gonadotropin hormone therapy, and corneal and meningeal transplants (Budka
& Will, 2015). Sizeable outbreaks of iatrogenic CJD have occurred after distribution of
contaminated dural graft material and human growth hormone. Since 1985, over 100 cases of
CJD have occurred 16 months to 18 years after surgical use of human cadaveric dura mater
(Brown et al., 2000). Over 8000 children and adolescents in the USA had received this
preparation. The product was withdrawn in most countries, and a recombinant human growth
hormone was quickly licensed. Since then, however, over 130 young adults have developed CJD
5–30 years after discontinuing injections (Brown et al., 2000). The long incubation period after
growth hormone injections presumably reflects the peripheral route of inoculation in contrast to
intracerebral placement of contaminated dura mater. In both situations, homozygosity at codon
129 seems to increase susceptibility to iatrogenic disease (Brown et al., 2000).

17. 2.2.4 Variant CJD
In 1994, a new form of human spongiform encephalopathy emerged in the UK. Over the past
decade, the CJD Surveillance Unit in Edinburgh has reported 150 cases of a new variant of CJD
in the UK (Johnson, 2005). Patients have a course and pathology distinctive from other forms of
CJD: young age at onset, prominence of psychiatric and sensory symptoms, and long disease
course. Neuropathological examination shows widespread vacuolisation with many plaques of
abnormal prion protein. All cases tested have been homozygous at codon 129 for methionine
(Will et al., 2000; Peden & Ironside, 2004). Nine cases have been reported in France and there
have been isolated cases in several other countries.
Although the numbers in the UK seem to have subsided since 2000 (Andrews et al., 2003),
concern persists whether the polymorphism at 129 represents a susceptibility determinant to
infection or a determinant of the incubation period; in the latter case a future second wave of
disease would be expected.
The prions from the variant disease seem to be of common origin: they have similar localization
and incubation periods in strains of inbred mice and similar western blot patterns. Prions from
patients with variant CJD share these signatures with those from cattle with BSE, indicating that
they have a common source (Bruce et al.,1997). Cattle were likely infected by feed and people
were probably infected by the consumption of beef. Although this route is probably true, human
beings, like cattle, are exposed directly to products of the rendering industry (Johnson, 2005).
The derived tallow is used in cosmetics that could lead to conjunctival or mucous membrane
exposure, in soap that can come into contact with skin abrasions, and in gelatin that can lead to
oral exposure. Furthermore, bone meal produced by rendering is a component of gardening
products, such as dusting powder for roses, which could lead to olfactory exposure.
2.2.5 Kuru
This disease appeared in the earlier part of the 20th
Century among members of the "Fore" tribe,
in the Eastern Highlands of Papua New Guinea, to the east of the Pacific Ocean. The name
"Kuru" is the local name used by fore people to describe the condition. It means "laughing death"
in their language because it is accompanied by uncontrollable laughter.
Kuru is an invariably fatal disease, and like other TSEs it affects both mental and motor
functions. Its incubation period ranges between 2-40 years, but is usually several years long.

18. However, the clinical course of the disease is relatively short - the patient dies within 3 months to
one year, at the most, after the appearance of symptoms. The symptoms include: in coordination
of movement, stumbling, muscle tremors, difficulty in articulating words, involuntary oscillation
of the eyes (nystagmus), difficulty to swallow, inability to hold things and finally dementia and
death. The disease was associated with cannibalism (eating the brain of dead humans) and spread
between members of the tribe, affecting more women and children than male adults. It is
generally believed that Kuru is now extinct (Nair & Johnson, 2011).
2.2.6 Gertsmann-straussler-scheinker syndrome (GSS)
GSS is a very rare, usually familial, fatal neurodegenerative disease that affects patients from 20-
60 years of age (Prusiner, 1995). This prion disease is caused by the inheritance of a PRNP gene
with a mutation encoding most commonly, leucine instead of proline at position 102 (P102L) or
valine instead of alanine at position 117 (A117V). The disease is strongly associated with
homozygosity for a polymorphism at position 129 (both residues being Methionine). Brain
extracts from patients with GSS can transmit the disease to Monkeys, apes and transgenic mice
containing a portion of the human PRNP gene. Transgenic mice expressing the P102L gene
develop the disease spontaneously (Prusiner, 1997).
GSS occurs typically in the 4th-5th decade, characterized by cerebella ataxia and concomitant
motor. Problems, dementia less common and disease course lasts several years to death. It was
originally thought to be familial, but it is now known to occur sporadically as well (Heaphy,
1998; Obi & Nwanebu, 2008).
2.3 ANIMAL PRION DISEASES
2.3.0 Scrapie of sheep
Scrapie the first TSE to be studied was described in sheep and goats in the 18th century,
precisely in 1732. However it is still found in most parts of the world despite attempts to
eradicate the agent by destroying the infected flock (Prusiner, 1997; Schwartz, 2004). Scrapie is
a fatal, degenerative disease that affects the nervous system of sheep and goats. It is one of
several transmissible spongiform encephalopathies, which are related to bovine spongiform
encephalopathies (BSE) and chronic wasting disease (CWD) of deer and elk. Like other TSEs,

19. scrapie is also caused by prions (Gee, 1996). The name scrapie was derived from one of the
symptoms of the condition, wherein affected animals will compulsively scrape off their fleece
aganist rocks, trees or fences. The disease apparently causes an itching sensation in the animals.
Other symptoms include excessive lip smacking, strange gait and convulsive collapse
(Weissmann, 2004; Johnson, 2005).
Scrapie is infectious and transmissible among similar animals in feed contaminated with nerve
tissue and so one of the most common ways to the disease (since it is incurable) is to quarantine
and destroy those affected. However it tends to persist in flock and can also arise apparently
spontaneously in flocks that have not previously had cases of the disease. The mechanism of
transmission between animals and other aspects of the biology of the disease are only poorly
understood. Recent studies suggest that scrapie agents. Suggest that scrapie agents may be spread
through urine and persist in the environment for decades (Obi & Nwanebu, 2008). Scrapie
agent, in the form of extracts from infected brains, has been passed experimentally to mice,
hamster, ferrets, mink, and monkeys, but apparently is not infectious for humans, chimpanzees
or rabbits (Obi & Nwanebu, 2008). Vertical transmission may occur, but exposure of young
lambs to infected flocks seems to be the major risk factor. The infection crosses species barriers
to goats that share pastures with affected sheep, but no evidence implicates natural spread to
other livestock or to people. The disease has been experimentally transmitted to primates,
rodents, and other species (Johnson, 2005).
2.3.1 Transmissible mink encephalopathy (TME)
Transmissible mink encephalopathy is a rare disease of ranch-raised mink that is caused by
exposure to a scrapie-like agent in feed (prion). Transmission of TME to hamsters resulted in the
identification of two clinically different syndromes, HYPER and DROWSY. Differences in the
physicochemical properties of PrP from these two strains suggests that PrP plays an important
role in defining strains (McKenzie, Bartz & Marsh, 1996)

20. 2.3.2 Chronic wasting disease of cervids
Chronic wasting disease (CWD) is a unique transmissible spongiform encephalopathy (TSE) of
mule deer (Odocoileus hemionus), white-tailed deer (O. virginianus), and Rocky Mountain elk
(Cervus elaphus nelsoni). The natural history of CWD is incompletely understood, but it differs
from scrapie and bovine spongiform encephalopathy (BSE) by virtue of its occurrence in
nondomestic and free-ranging species. CWD has many features in common with scrapie
(Williams, 2005). Chronic wasting disease of deer (cervids) was first found in the 1960s among
captive mule deer in a wildlife research facility in Colorado, USA. The clinical disease occurred
in deer 2·5–4·0 years after entering the facility as fawns or young adults. Animals became
emaciated, and developed behavioural changes, unsteadiness, and excessive salivation. Death
occurred within weeks to months, and pathological examination of brains showed widespread
spongiform changes in grey matter. Elk in contact with mule deer developed the disease, and the
disease was experimentally transmitted to various species, including limited evidence of
transmission to squirrel monkeys and cows (Johnson, 2005).
2.3.3 Bovine spongiform encephalopathy
There are several theories regarding the cause of the first reported case of BSE in the mid-1980s;
some insist that the BSE pathogen (PrPSc) formed naturally and others claim that the disease
was caused by the cow feed made from sheep infected with scrapie. By an extensive
epidemiologic investigation, the main cause for BSE turned out to be a meat and bone meal
(MBM) made from the discarded bones and intestines of slaughtered cows and sheep (Lee, Kim,
Hwang, Ju & Woo, 2013).
In 1985, the first cases of BSE were observed in the UK; in the next decade a massive epidemic
throughout the country led to infection of about 1 million cows (Johnson, 2005).
In the UK, in particular, cow intestines have been used in MBM as a protein supplement since
1972, which accelerated the increase of the occurrence of BSE (Lee, Kim, Hwang, Ju & Woo,
2013) Export of cattle and feed spread the disease to Europe and to scattered countries around
the world. This was apparently an extended common source outbreak, and the source was
evidently the contamination of meat-and bone meal fed to young calves. The initial hypothesis
assumed that scrapie in infected sheep carcasses rendered into bone meal crossed a species
barrier causing infection in calves and disease in cows age 4–5 years. Subsequent rendering of

21. cattle carcasses fuelled the epidemic. An alternative hypothesis is that a sporadic case of BSE in
a cow could have initiated the epidemic.
Hundreds of thousands of infected animals have been eaten by Europeans and particularly the
British over the past years. Research work suggests that the infected meat may pose a threat to
human health, but the significance of that threat may not become apparent for years. The US
Department of Agriculture claims that BSE has not been identified in any US cattle so far12,
hence it is generally considered a British problem (Kalikiri & Sachan, 2003).
2.4 Risk Assessment
Prion diseases in both animals and humans show great remarkable similarities. They have long
incubation periods; present as progressive fatal neurological diseases with motor, sensory, and
cognitive deficits; cause similar spongiform pathology limited to the CNS; result from
misfolding of a normal membrane glycoprotein; and evoke no immune response due to the fact
that the body recognizes the prion protein as a part of the body component and not a foreign
body (antigen). Despite these shared features predicting risk of acquisition or spread of disease is
complicated by the striking differences in mode and ease of transmission, unpredictable species
barriers, differing distribution of the agent in the body, and strain variations.
2.5 Natural Transmission
Both infectious and genetic transmission can occur in nature. Food-chain infection is paramount
for Kuru, transmissible mink encephalopathy, and BSE. In contrast, these three diseases do not
seem to spread easily in the field, unlike scrapie and chronic wasting disease, although some
horizontal transmission or intrauterine infection of BSE might have occurred but remained
hidden by the food-borne epidemic. Genetic transmission has been documented only with
familial CJD; genetic transmission in animals has not been observed. Vertical transmission with
intrauterine infection has also not been definitely established with any prion disease.

22. Table 1: The Prion diseases (Prusiner, Scott, DeArmond, & Cohen, 1998)
NATURAL TRANSMISSION OF PRION DISEASES
DISEASE MODE OF TRANSMISSION
Scrapie Exposure of lambs to infected sheep
CWD Pasture contamination
Kuru Endocannibalism
BSE Meat-and-bone meal fed to calves
TME Feed and possibly cannibalism
Vcjd Probable consumption of infected cattle
fCJD Mutations in PRNP
sCJD Unknown
GSS Inheritance of a PRNP gene with a mutation
Sporadic CJD remains the oddity in which evidence does not implicate either lateral or genetic
transmission. Judging from the spread of other prion diseases transmission from zoonotic
diseases or other affected humans would seem plausible. The lack of data incriminating contact
transmission has led to the speculation of endogenous generation of prion proteins—reminiscent
of ―spontaneous generation‖.
2.6 Species Barriers
It has been known for many years that transmission of prion strains between species is restricted
by a ―species barrier‖. This is demonstrated by an increase in incubation period, and a decrease
in the percentage of animals succumbing to disease, when prions from one species are inoculated
into another (―first passage‖). This contrasts with the situation when prions are inoculated into
animals of the same species, when these animals are seen to all become sick, with remarkably
consistent incubation periods. If after inoculation into a different species infectious tissue is
taken from the animals that do become sick and transmitted to further animals (―second
passage‖), the pattern of infectivity seen resembles that of the initial species, with most if not all
animals becoming sick after relatively short and consistent incubation periods. This transmission
barrier between species can be quantified by the difference in incubation period and rate of
infection between first and second passages (McKintosh, Tabrizi & Collinge, 2003).

23. Transmission to another species, however, may generate species-specific prions that can no
longer be transmitted to the original species or that can facilitate spread. For example, human
Kuru and CJD brain tissue do not transmit disease to goats or ferrets, but if transmitted to
primates or cats the primate or cat tissue will transmit to goats and ferrets. There are many
examples of this patchwork pattern of species barriers (Brown, Will, Bradley, Asher & Detwiler,
2001).
Some species seem protected whereas others—such as mice, hamsters, and primates—have been
susceptible experimental hosts to various prion diseases of other species. In the UK, the public
was reassured that BSE would not spread to people; an assumption based on hundreds of years of
eating scrapie-infected mutton with no evidence of gastrointestinal transmission of this ruminant
disease across the species barrier to humans. However, BSE did cross a similar species barrier
(Johnson, 2005).
2.7 The concept of prion strains
Prion strains are defined as infectious isolates exhibiting distinct incubation times and prion
disease phenotype in the same host. Strains cannot be encoded by differences in the primary
structure of PrP (Collinge & Clarke, 2007; Kovacs, & Budka, 2009).
In conventional pathogens strains are distinguished by differences in their nucleic acid genome.
In contrast in prion disease, this is most likely related to different conformational states of PrP
that includes also differential proteinase K digestion kinetics. Three principal PrP glycoforms are
associated with prion strains; both PrPC and PrPSc exists in three main glycosylation states:
mono-, di and unglycosylated forms (Parchi et al., 1999). These are widely used as molecular
indicators of prion strain typing. To support the notion of strains and also the ‗protein-only‘
hypothesis, so called synthetic prion strains have been developed and described (Legname et al.,
2004). The question arises whether these are in fact infectious prions or are simply capable of
seeding prion protein production in hosts that have high levels of PrPC and are close to develop a
spontaneous disease. In humans the polymorphism at residue 129 constrains which prion strains
may propagate, although the exact mode needs clarification. Diversity of prion strains has been
demonstrated in several mammals and has been discussed also in relation with the species barrier
(Aguzzi, Heikenwalder, & Polymenidou, 2007). The latter means that prions isolated from one
species may be less infectious to other species.

24. That such isolates could be propagated through multiple passages in mice suggested that the
scrapie pathogen has a nucleic acid genome that is copied and passed on to nascent prions. But
no evidence for scrapie-specific nucleic acid encoding information that specifies the incubation
time and the distribution of neuropathological lesions has emerged from considerable efforts
with a variety of experimental approaches as described above. In striking contrast, mice
expressing PrP transgenes have demonstrated that the level of PrP expression is inversely related
to the incubation time. Furthermore, the distribution of CNS vacuolation and attendant gliosis are
a consequence of a pattern of PrPSc deposition that can be altered by both PrP genes and non-
PrP genes. These observations taken together begin to build an argument for PrPSc as the
information molecule in which prion strain-specific information is encrypted. Deciphering the
mechanism by which PrPSc carries information for prion diversity and passes it on to the nascent
prions is a challenging goal. Whether PrPSc can adopt multiple conformations, each of which
produces prions exhibiting distinct incubation times and patterns of PrPSc deposition, remains to
be determined (DeArmond & Prusiner, 1995).
2.8 Molecular Mechanisms of Prion Disease Pathogenesis
The intracellular accumulation of PrPSc seems to be responsible for the pathogenesis of prion
diseases. Although extracellular deposits of PrPSc are seen as PrP amyloid plaques, they are not
an obligatory feature of the disease. The precise subcellular sites of PrPSc accumulation in brain
are not well defined. Presumably, PrPSc is deposited in neurons, and evidence exists for the
transport of both PrPc and PrPSc along axons. In scrapie-infected cultured cells, PrPSc is found
primarily in secondary lysosomes (Aguzzi, & Heikenwalder, 2006), and some investigators have
suggested that similar sites of PrPSc deposition occur in brain, but the data are less convincing.
The lack of conformation dependent PrPSc-specific antibodies has hampered such studies. The
first link between PrP and the neuropathology of prion diseases came during the characterization
of brain fractions highly enriched for scrapie infectivity.
Such fractions were found to contain one protein, PrP 27-30, and rod-shaped particles that
proved to be indistinguishable from amyloids on the basis of ultrastructural and tinctorial criteria.
This finding was extended to the brains of rodents with a-PrP antiserum, which stained amyloid
plaques. Such findings were initially greeted with great skepticism as amyloids are composed of
proteins found in animals and not of viral proteins (DeArmond, & Prusiner, 1995).

25. CHAPTER THREE
3.0 CONCLUSION
Statistics observed from related literature has proven that prion related diseases are either not
observed or recorded in Africa as in many parts of the world; Kuru, seems to be the only prion
related disease associated with the black continent. Of late, research has suggested that
epidemics of human TSEs may have occurred for thousands of years (McKintosh, Tabrizi, &
Collinge, 2003). Despite these statistics, it is the potential threat of an epidemic of nvCJD in the
UK population that has provided an increased momentum to try to understand these refreshingly
new and dynamic diseases. Animal TSEs are now recognized to occur across all countries,
African countries inclusive (with the exception of Australia and New Zealand), and to occur not
only as scrapie in sheep, but as transmissible mink encephalopathy, BSE in cows, FSE in
domestic cats, and zoo animals, and as chronic wasting disease in American deer and elk herds.
Infectious diseases are not known for their tendency to respect national borders; BSE has already
spread through many European countries and vCJD may therefore still do so. The past few years
have seen major increases in our understanding of the etiology and pathology of prion diseases
but large research challenges still remain, if a major epidemic of vCJD is to be avoided and
suitable treatments are to be found. Not least among these are proof of the exact nature of this
novel infectious agent, further elaboration of the role of PrPc, and the development of reliable
therapeutics. For Africa to stay secured against the fatal neurodegenerative disease, all countries
in the continent most be very careful on importation and consumption of meat of cows, sheep
goats, deer, etc. from other countries especially European countries. Care must be taken on using
MBM to feed other animals and Prion, prion disease and prion associated research laboratories
should be setup to continually investigate this misfolded protein mishap.

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