Prions

Characteristics of Kuru

It was called the laughing death It was most likely acquired through ritualistic cannibalism

Effective prion decontamination relies upon?

Protein hydrolysis Reduction or destruction of protein tertiary structure Bleach, caustic soda, and strong acidic detergents

What is the central dogma of molecular biology?

DNA --> RNA --> Protein

What is the progression of the disease?

1. A long incubation period (several years) which has given rise to the term "slow infection. 2. Loss of muscle coordination which leads to a difficulty in walking, indicating a functional disorder of the cerebellum. 3. Dementia characterized initially by loss of memory, diminished intellect and poor judgement. 4. Progressive insomnia characterized by a marked reduction or loss of the slow-wave and rapid-eye-movement phases.

Kuru originated where?

1st studied in the 1950s It was first known epidemic of human prion disease It is isolated Fore tribes in the highlands of New Guinea

What is a prion?

A prion has been defined as "small proteinaceous infectious particles which resist inactivation by procedures that modify nucleic acids

Treatments for prions?

All known prion diseases affect the structure of the brain or other neural tissue and all are currently untreatable and are always fatal

Amyloid

All known prions induce the formation of an amyloid fold, in which the protein polymerizes into an aggregate consisting of tightly packed beta sheets.

Prions propagate how?

All such agents have been discovered to propagate by transmitting a mis-folded protein state

What is an amyloid?

Amyloids are insoluble fibrous protein aggregates

Other Prion model

An alternative model assumes that PrPSc exists only as fibrils, and that fibril ends bind PrPC and convert it into PrPSc. If this were all, then the quantity of prions would increase linearly, forming ever longer fibrils. But exponential growth of both PrPSc and of the quantity of infectious particles is observed during prion disease

What are the symptoms of mad cow?

Degenerative central nervous system diseases The diseases are characterised by loss of motor control, dementia, paralysis, wasting and eventually death, typically following pneumonia Visible end results at post-mortem are non- inflammatory lesions, vacuoles, amyloid protein deposits and astrogliosis.

How was Mad Cow diagnosed?

Diagnosis Examination of brain biopsies Immunofluorescence test on tonsillar biopsies Western blot

In animals what are the transmissible forms of spongiform encephalopathies

Animals Scrapie (sheep and goats) Bovine spongiform encephalopathy (BSE) Chronic wasting disease (mule, deer, and elk) Transmissible Mink encephalopathy All caused by misfolded proteins

What is the name of the sporadic form of prion disease in humans?

Besides having a genetic origin, other human forms of prion diseases can be sporadic, as in sporadic CJD, as well as foodborne. That is, they are contracted when people eat products contaminated with mad cow disease. This form of Creutzfeldt-Jakob disease is called variant CJD or vCJD

What are features of TSE?

Characterized by four features: Spongiform change TIssue section of brain is full of holes Neuronal loss Astrocytosis The star-ship cells in the brain, important in blood brain barrier Keep neurons happy, but if neuronal loss they increase to attempt to repair neuronal loss Amyloid plaque formation Insoluble fibrous proteins within the central nervous system

How is it transmitted?

Genetic, Sporadic or Infectious via ingestion of infected foodstuffs and via iatrogenic means (e.g. blood transfusion).

Problem with the heterodimer model?

Heterodimer model requires PrPSc to be an extraordinarily effective catalyst, increasing the rate of the conversion reaction by a factor of around 10^15 This problem does not arise if PrPSc exists only in aggregated forms such as amyloid, where cooperativity may act as a barrier to spontaneous conversion.

How are prions transmitted?

Horizontal transmission Familial (genetic) Sporadic, with no known history of exposure

What is human mutation for the prion disease?

Humans with prion protein gene mutation is called the Creutzfeldt-Jakob disease, also called genetic CJD for short.

WHO procedure for prion decontamination

Immerse in 1M NaOH or 5% sodium hypochlorite (bleach) for 1 hour Remove and rinse in water Then transfer to an open pan and heat in a gravity-displacement (121oC) or in a porous-load (134oC) autoclave for 1 hour Clean Then perform routine sterilization processes

What is the progression of Mad Cow?

In 4 -5 years the disease begins to appear After 4 months of symptoms, death is near in the myoclonic stage

In humans what are the transmissible forms of spongiform encephalopathies

Kuru Acquired form from cannibalism Creutzfeldt-Jakob disease (CJD) Most common type, it can arise from all three forms Gerstmann-Straussler-Scheinker syndrome Very rare, autosomal dominant inheritance. Alpers syndrome

What was the cause of Mad Cow?

Mad cow disease can be caused by a genetic mutation within a gene called Prion Protein Gene.

Are TSEs mostly sporadic?

Most TSEs are sporadic and occur in an animal with no prion protein mutation. Not by casual contact but by infected tissue, body fluids, or contaminated medical instruments. You need protein denaturing methods to prevent prion transmission

How to prevent transmissible encephalopathies

No treatments available Stop cannibalism Eliminate sick animal from livestock feed Neurosurgical tools disinfected in 5% hypochlorite or 1 M NaOH or autoclaved at 15 psi for 1 hr

Characteristics of a Prion

No virion structure or genome It was first thought it was a virus. Elicits no immune response Extremely resistant to inactivation by heat, disinfectants & radiation Can even survive autoclaving You need to hydrolyze the protein to destroy the protein

Which Prp is the most stable?

PrPSC is extremely stable and accumulates in infected tissue, causing tissue damage and cell death

Prp(sc)

PrP^sc refers to the misfolded form of PrP, that is responsible for the formation of amyloid plaques and neurodegeneration.

PrP(c)

PrPc refers to the endogenous form of prion protein (PrP), which is found in a multitude of tissues

What are prion diseases?

Prion diseases cause spongiform encephalopathies because of the post mortem appearance of the brain with large vacuoles in the cortex and cerebellum. Probably most mammalian species can develop these diseases.

What does prion refer to?

Prion refers to the theoretical unit of infection.

How do prions cause neuro disorders?

Prions cause neurodegenerative disease by aggregating extracellularly to form plaques known as amyloid, which disrupt the normal tissue structure

Can a prion renature?

Renaturation of a completely denatured prion to infectious status has not yet been achieved, however partially denatured prions can be renatured to an infective status under certain artificial conditions.

What was done to prevent mad cow disease?

Ruminant protein feed and bovine offals banned to prevent disease

Possible treatment?

Since the incubation period of prion diseases is so long, an effective drug does not need to eliminate all prions, but simply needs to slow down the rate of exponential growth

Who discovered prions?

Stanley Prusiner

How do you sterilize prions?

Sterilizing prions therefore involves the denaturation of the protein to a state where the molecule is no longer able to induce the abnormal folding of normal proteins Resistant to proteases, heat, radiation, and formalin treatments although their infectivity can be reduced by such treatments.

What is surprising about prions?

The discovery that proteins alone can transmit an infectious disease, it was a surprise in the scientific community

Does the protein self replicate?

The protein itself does not self-replicate and the process is dependent on the presence of the polypeptide in the host organism

How did Mad Cow occur?

The use of meat and bone meal, produced from the ground and cooked left-overs of the slaughtering process as well as from the cadavers of sick and injured animals such as cattle, sheep, or chickens, as a protein supplement in cattle feed was widespread in Europe prior to about 1987

Mechanism for prion disease Heterodimer model

This model assumed that a single PrPSc molecule binds to a single PrPC molecule and catalyzes its conversion into PrPSc. The two PrPSc molecules then come apart and can go on to convert more PrPC. However, a model of prion replication must explain both how prions propagate, and why their spontaneous appearance is so rare.

PrP

abbreviation for protease resistant protein.