PRION DISEASES

Transmissible Spongiform Encephalopathy

(TSE)

Dr. Durgadas Govind Naik

Update : December 2016

PRIONS :

Prions: Proteinaceous infectious particles

(pronounced as “preeons”)

Causative agents cause fatal degenerative disorders of

central nervous system of humans and other animals.

Unique among infectious agents:-

they have no nucleic acids (RNA or DNA)

Stanley Prusiner and his associates (1983) studied

scrapie disease in sheeps.

The name of the disease comes from-infected

sheep under neurological disorder start scraping their

skin against rocks resulting in loss of wool.

Scrapie Sheep

The existence of an infections agent

composed only of protein,

defy scientific dogma of central dogma

of molecular biology.

Characteristics of Prion Proteins :

Size : ~253 amino acids

Made up of only protein and without nucleic acids(RNA,DNA).

These self replicate without RNA or DNA.

Inactivated by proteases, urea, detergents, Phenol

Resistant to nucleases, formaldehyde, Beta propiolactone,

UV irradiation & heat at 80o C, but are inactivated at 125o C

Prion protein doesnot replicate from scratch.

It causes another protein to change its shape and

there by becomes a “prion”.

Spongiform

encephalopathy

CJD: severe

brain atrophy

Cerebellar

degeneration

A prion protein (PrPsc) is an altered form of a

normal host protein (PrP) or (PrPc) .

Nomal host surface protein is present in neurons and

its exact function is not known.

Evidence suggest that it may have a role in cellular

signaling, and protects against neurodegeneration

by its anti-apoptotic activity

Prion has the capacity to change the secondary

structure of a molecule of PrP, so that it too becomes

a “Prion” .

Secondary structure of PrP is largely made up

of -helices, and that of “Prion” by -sheets.

Excretion of Prion proteins

excretion of prion through multiple routes such as

from skin, feces, urine, milk, nasal secretions,

saliva and placenta.

excreted scrapie agent is detected within

environmental samples such as water and on the

surfaces of inanimate objects.

PrP = Precursor protein (PrPc = Cellular protein).

PrPsc = Protein”P” infectious protein of scrapie

(prion protein of scrapie)

When prion enters host, it forms more prions

from the cell’s supply of PrP.

Prions accumulate, aggregate into fibrils,

penetrate nervous tissue (brain) and cause disease.

Brain is full of pores and becomes spongy

PrP = PrPc (cellular)

Prion 6:4, 322-333; September/October 2012; ©

2012 Landes Bioscience

The cascade of prion entry, peripheral replication, neuroinvasion, and neurodegeneration.

Aguzzi A, Zhu C (2014) Five Questions on Prion Diseases. PLoS Pathog 8(5): e1002651. doi:10.1371/journal.ppat.1002651

http://journals.plos.org/plospathogens/article?id=info:doi/10.1371/journal.ppat.1002651

Prion diseases transmissible spongiform encephalopathy (TSE)

1. Scrapie- Sheep and Goats.

Causative agent 20-30nm long, resistant to UV,

formaldehyde, temperature upto 80 C for 60 mts.

Disease symptoms: CNS, paralysis and death

2. Kuru-Humans,

Disease due to cannibalism practiced by people of

Papua New Guinea. Kuru was transmitted by

ritualistic cannibalism,

where people honored their dead by eating parts

of the body, including infected brain.

Now, the practice is stopped & disease also disappeared.

Incubation period: 4-20 years.

Inoculation of infected brain tissue into

monkey-caused disease in 2 years.

Disease symptoms:

CNS, unsteadiness,disordered behavior.

3. Mad cow disease (Bovine Spongiform Encephalopathy)

BSE thought to be a form of Scrapie “ that was

transmitted to cattle through processed

sheep tissues in cattle feed.

To stop the spread of BSE, cattle were slaughtered,

as a result disease disappeared.

Prion infected brain tissues manifest holes (plaques),

which contain numerous prion particles and

become spongy in appearance.

Hence the name of the disease.

Incubation period: Long- may be many years.

Disease symptoms: Depression, unusual behavior,

softening of brain tissue and death in one year.

• Number of cattle confirmed with BSE in the United Kingdom as of 2003 is >180,000.

• Total estimated number of U.K. cattle potentially infected with BSE is in excess of 2 million

• Approximately 750,000 BSE-infected cattle were estimated to have been slaughtered between 1980 and 1996

• >25 countries have reported the presence of BSE in cattle

• The leading hypothesis for the origin of BSE is cross-species transmission of scrapie to cattle via the feeding of meat-and bone meal that was contaminated by the inclusion of scrapie-infected sheep parts.

• And to Humans by contaminated/infected beef

4. Creutzfeldt-Jakob Disease (CJD)

( variant CJD, new variant nvCJD) in Humans (incidence 1 case per Million)

Transmitted by

- corneal transplants,

- contaminated surgical instruments,

- beef or beef products containing prion particles,

- by injection of growth hormones prepared

from human pituitary.

Hospital Acqured Infection : contaminated surgical

instruments

Disease: formation of lesions in the CNS,spinal cord

manifesting neurological symptoms.

Progressive spastic of limbs and

involuntary movements of limbs.

After onset of symptoms-death.

How many people treated with pituitary hGH got CJD in

other countries?

Of the approximately 7,700 people in the United States

who received pituitary hGH, 29 had CJD.

In France, 119 people got CJD (out of 1,700 people treated

with pituitary hGH.

In the United Kingdom, 75 people (out of 1,849)

In New Zealand, 6 people (out of 159)

Holland and Brazil have each had two people got CJD.

Austria, Qatar, Ireland have each had one person got CJD.

In Australia, one person got "possible" CJD.

CJD can be grouped into classic or new variant disease.

The classic types of CJD are:

Sporadic CJD makes up the majority of cases.

It occurs for no known reason.

Average age at onset is 65

Familial CJD results when a person inherited the

abnormal prion (inherited CJD is rare)

However, new variant CJD (nvCJD) is an infectious form

that is related to mad cow disease.

The infection responsible for the disease in cows is believed

to be the same one responsible for vCJD in humans.

New variant CJD accounts for less than 1% of cases, and

tends to affect younger people.

• It can result when someone is exposed to contaminated products.

• Other nvCJD cases have occurred when people were given - corneal transplants from infected donors,

and

• from contaminated electrodes that were used in brain surgery

The human prion diseases are: Creutzfeldt-Jakob disease.

Sporadic-sCJD, familial-fCJD, iatrogenic-iCJD,

and variant-vCJD)

Kuru. A now-extinct disease of New Guinea natives,

transmitted by eating the brains of dead persons

who had the disease.

Gerstmann-Straüssler-Scheinker syndrome (GSS).

A slowly progressive ataxia ( lack of voluntary coordination

of muscle movement) and dementia, (loss of mental functions

such as thinking, memory, and reasoning ) characterized by

widespread PrPTSE amyloid plaques throughout the CNS.

Fatal familial insomnia (FFI). An autosomal dominant

sleep disorder with pathological lesions in the thalamus.

Classic CJD Classic CJD is a human prion disease. It is a

neurodegenerative disorder with characteristic

clinical and diagnostic features.

vCJD vCJD has a different clinical and pathologic

characteristics from classic CJD. Each

disease also has a particular genetic profile

of the prion protein gene

The most common animal prion diseases are:

Scrapie. An important disease of sheep that has been known for

over 100 years. Sick animals rub against rocks or other hard

surfaces, scraping their fleeces. The discovery of transmissibility and

other important aspects of the biology of prion diseases was based

on knowledge of scrapie.

Bovine spongiform encephalopathy (BSE)-

mad cow disease.

Wasting disease of deer Prion diseases have also been reported in several other domestic

and wild animalss and can cross from one species to another.

Experimental transmission to primates and guinea pigs has played an

important role in elucidating their pathogenesis.

Hallmark of vCJD in brain tissue is the

presence of rounded deposits of abnormal

proteins surrounded by vacuoles, called florid

plaques

Diagnosis ; Currently, the certain diagnosis of human prion disease

requires finding PrPSc in the CNS by biopsy or autopsy .

Creutzfeldt–Jakob disease (CJD)

1. In CSF: Search for the presence of 14-3-3 and tau, two proteins

2. In DNA extracted from blood, brain, or other tissues:

Search for the presence of mutation in the prion protein gene

and determine the polymorphism at codon 129.

3. In unfixed brain tissue obtained either at biopsy (?)or autopsy:

Search for the presence and establish the type of the abnormal,

protease-resistant form of the prion protein

4. On fixed brain tissue: microscopic examination by histological

and immunohistochemical demonstration of the prion protein, as

well as pattern of tissue distribution