Misfolded proteins which catalyses the refolding of the native protein into the misfolded pathogenic forms are called as Prions. They are responsible for fatal neurodegenerative diseases. Some of the neurodegenerative diseases such as Scrapie, BSE, CWD of animals and Kuru, CJD, Fatal familial insomnia of human beings are included in the presentation.

1. DISEASES CAUSED BY
PRIONS
Presented by:
Megha Varshini Gowda B R

2. INTRODUCTION
• Prion diseases or Transmissible Spongiform Encephalopathies
(TSEs) are fatal neurodegenerative disorders.
• In 1939 Cuille and Chelle hypothesized Sheep disease Scrapie
was caused by “Slow virus”.
• J.S.Griffith was the first scientist to boldly speculate that the
Scrapie agent was proteinaceous.
• Stanley B.Prusiner coined the term “Prion” to describe the
infectious Scrapie agent for which he won Nobel Prize in 1997.
• Prusiner and Charles Weissman discovered that a host cellular
gene encodes the prion protein.
• Some of the diseases are Scrapie, Bovine Spongiform
Encephalopathy(BSE), Chronic Wasting Disease(CWD), Kuru,
Creutzfeldt-Jakob disease (CJD), and fatal familial insomnia
(FFI).

3. MOLECULAR BIOLOGY OF PRIONS
The evidence that prions are not conventional viruses:
• Resistance to heat inactivation: Infectivity is reduced but not
eliminated by high-temperature autoclaving .
• Resistance to radiation damage: The Scrapie agent was highly
resistant to both ultraviolet light and ionizing radiation,
indicating that any nucleic acid present must be less than 80
nucleotides.
• Resistance to DNAse and RNAse treatment and to
Zn2+catalyzed hydrolysis, all of which treatments inactivate
nucleic acids.
• Sensitivity to urea, SDS, phenol, and other protein-denaturing
chemicals.

4. STRUCTURE AND FUNCTION OF
PRION PROTEIN
• PRNP is the human gene encoding for the major prion protein
PrP, also known as CD230 (cluster of differentiation 230).
• The human PRNP gene is located on the short (p) arm of
chromosome 20 between the end (terminus) of the arm and
position 12, from base pair 4,615,068 to base pair 4,630,233.
• The primary sequence of PrP is 253 amino acids long, post
translation results in a mature length of 208 amino acids.
• Although the precise function of PrP is not yet known, it is
possibly involved in the transport of ionic copper to cells from
the surrounding environment and cell signaling or in the
formation of synapses.

5. Figure 1:

6. MULTIPLICATION OF PRIONS
It “replicates” by converting native prion proteins that already
exist in the host cell into the pathogenic form. Mechanism of
prion misfolding:
1. Neuronal cells produce the native form of the prion protein.
2. The pathogenic form of prion protein catalyses the refolding of
the native prions into the pathogenic forms.
Figure 2: Replication of prions.

7. Figure 3: Heterodimer model for prion replication.

8. 3. The pathogenic form is protease resistant, insoluble and forms
aggregates in neural cells.
4. This eventually leads to destruction of neural tissues and
neurological symptoms.
Figure 4: A-Mode of action of Protease K on PrPC and PrPSc . B-Conversion of PrPC to PrpSc .

9. PRION DISEASES
• These are the group of invariably fatal neurodegenerative
diseases mediated by entirely novel mechanism.
• Prion diseases may present as genetic, infectious or sporadic
disorders.

10. SCRAPIE
• Scrapie is a fatal infectious disease that affects the central
nervous system of sheep and goats.
• First recognized in 18th century in Great Britain and Western
Europe.
• Scrapie is the oldest known and most widespread TSE.
Figure 5: Scrapie infected sheep.

11. Symptoms
Infected sheep show severe and progressive neurological
symptoms such as abnormal gait; they often repeatedly scrape
against fences or posts, a behavior from which the disease takes
its name. The incidence of the disease increases with the age of
the animals.

12. BOVINE SPONGIFORM
ENCEPHALOPATHY (BSE)
• BSE commonly referred to as mad cow disease is a transmissible
spongiform encephalopathy that affects cattle.
• Research indicates that the first probable infections of BSE in
cows occurred during the 1970’s with two cases of BSE being
identified in 1986.
• BSE possibly originated as a result of feeding cattle meat-and-
bone meal that contained BSE-infected products from a
spontaneously occurring case of BSE or scrapie-infected sheep
products.
• Strong epidemiologic and laboratory evidence exists for a causal
association between a new human prion disease called variant
Creutzfeldt-Jakob disease (vCJD) that was first reported from the
United Kingdom in 1996 and the BSE outbreak in cattle.

13. Symptoms
BSE results in changes in temperament, such as lack of
coordination and difficulty in rising, decreased milk
production or loss of body weight despite continued appetite.
Early in the clinical course of the disease, symptoms may be
slight, undetectable or unrecognizable.
Figure 6: BSE affected cattle.

14. CHRONIC WASTING DISEASE (CWD)
• Chronic wasting disease is a transmissible spongiform
encephalopathy of cervids such as deer, elk, and moose.
• It is the only TSE known to occur in free-ranging animals.
• CWD was first recognized in captive deer and elk in the
Western United States in 1967 and appears to be endemic in
origin.
• Another concern is that prions of chronic wasting disease
could be transmitted to cows grazing in pastures contaminated
by cervids.
• It is not known how the disease is spread among cervids, but
transmission by grass contaminated with saliva and feces is
one possibility.

15. Symptoms
The most obvious and consistent clinical sign is weight loss,
excessive drinking and urination, excessive salivation, drooling
and grinding of the teeth.
Behavioral changes include repitive walking in set patterns,
decreased interaction with other animals, hyper-excitability and
nervousness.
Figure 7: Elk with Chronic Wasting Disease.

16. HUMAN TSEs
Human spongiform encephalopathies are placed into three groups:
infectious, familial or genetic, and sporadic, distinguished by how
the disease is acquired initially.
• Sporadic prion diseases: It is thought that PrPSc forms
spontaneously because of the occurrence of some error of the
metabolism in the brain cells. Sporadic Creutzfeldt - Jakob
disease (sCJD), sporadic fatal Insomnia (sFI).
• Familial prion diseases are defined by the presence of a
mutation in the PrPC gene. Examples- Familial Creutzfeldt-Jakob
Disease (fCJD), Fatal Familial Insomnia (FFI) and Gerstmann-
Sträussler- Scheinker disease (GSS).
• Acquired prion diseases are caused by exposure to exogenous
PrPSc through food ingestion or medical and surgical procedures.
Kuru -ritual cannibalism. The Variant CJD (vCJD) - consumption
of prion-contaminated meat from cattle with BSE.

17. KURU
• Kuru was the first human spongiform encephalopathy to be
investigated
• Carleton Gajdusek and colleagues studied the disease kuru,
found in the Fore people of New Guinea. The first cases were
recorded in the 1960’s and involved progressive loss of
voluntary neuronal control, followed by death less than 1 year
after the onset of symptoms.
• The key to the origin of the disease was provided by the
profile of its victims; it was never seen in young children,
rarely in adult men, and was most common in both male and
female adolescents and in adult women.
• The Fore people practiced ritual cannibalism as a rite of
mourning for their dead.
• The incubation period for kuru can be in excess of 30 years but
in most cases is somewhat shorter. The practice of ritual
cannibalism was discouraged in the late 1950s

18. Symptoms
This disease is characterized by cerebellar ataxia (defective
motion or gait) without loss of cognitive functions. Others
observed that lesions in the brains of humans with kuru were
similar to lesions in the brains of animals with scrapie.
Figure 8: Microscopic view of normal and Kuru infected brain tissue.

19. CREUTZFELDT-JAKOB DISEASE (CJD)
• Classic CJD is a human prion disease. Identified in 1920’s by
German neuroscientists Hans Gerhard Creutzfeldt and Alphons
Maria Jakob.
• Infection with this disease leads to death usually within 1 year
of onset of illness.
• In about 85% of patients, CJD occurs as a sporadic disease with
no recognizable pattern of transmission.
• A smaller proportion of patients (5-15%) develop CJD because
of inherited mutations of the prion protein gene.
• Types of CJD:
1. Sporadic CJD: spontaneous formation of PrP
2. Variant CJD: consuming meat from a cow that had BSE
3. Familial or inherited CJD: mutated gene is inherited to the next
generation.
4. Iatrogenic CJD: infection is accidently spread from someone
with CJD through medical or surgical treatment.

20. Figure 9: Comparison between (a) normal and CJD brain (b) normal and CJD brain tissue.

21. Symptoms
Neurological symptoms
• Loss of physical co-
ordination, which can affect
a wide range of functions
such as walking, speaking
and balance(ataxia)
• Muscles twitches and
spasms
• Loss of bladder control and
bowel control
• Swallowing
difficulties(dysphagia)
• Loss of speech and
voluntary movement.
Psychological symptoms
• Loss of memory, which is
often severe
• Aggressive behaviour
• Loss of appetite, which can
lead to weight loss
• Paranoia
• Unusual and inappropriate
emotional responses.

22. FATAL FAMILIAL INSOMNIA
• Fatal familial insomnia is a rare form of inherited prion disease
that mainly affects the thalamus.
• Discovered in 1974 in Italy by Dr.Ignazio Roiter.
• Fatal familial insomnia is thought to be the result of a point
mutation in PRNP at codon 178, which corroborates PrP’s
involvement in sleep-wake cycles.
Figure 10: Microscopic view of FFI affected braim.

23. Symptoms
• The first symptoms of FFI usually begin in mid-life and may
include progressive insomnia, weight loss, lack of appetite, too
high or too low body temperature, and rapidly progressive
dementia.
• Other symptoms may include panic attacks, phobias, ataxia,
severe confusion (delirium). The autonomic dysfunction
commonly seen in FFI patients includes hyperhidrosis,
hyperthermia, tachycardia, and hypertension.
• Cerebellar dysfunction, enacted dream states, myoclonus, and
pyramidal signs are also reported in affected patients.
• A loss of circadian rhythm in the production of growth
hormone, prolactin, and melatonin can occur.

24. TREATMENT FOR PRION DISEASES
• There are currently no therapeutics available to slow or stop
the neurodegeneration characteristic of transmissible
spongiform encephalopathies, although symptoms may be
mitigated by the drug L-dopa.
• A potential breakthrough came when researchers discovered
that the antimalarial drug quinacrine blocked accumulation of
infectious prions in cultured cells.
• Monoclonal antibodies specific for PrP inhibit scrapie prion
propagation in mice and delay the development of prion
disease.

25. REFERENCES
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Biology of Microorganisms. Thirteen Edition, Pearson Education Inc,
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Microbiology.Ninth Edition, McGraw Hill Companies, USA.
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Principles of Virology. Fourth Edition, American Society for Microbiology,
USA.
• Cann, A. J. (2012). Principles of Molecular virology. Fifth Edition, Elsvier
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