PRIONS

A disase-causing agent that is neither bactereial nor fungal nor viral and contains no genetic material. A prion is a protein that occurs normally in a harmless form. By folding into an aberrant shape, the normal prion turns into a rogue agent. It then coopts other normal prions to become rogue prions. Prions propagate by transmitting a misfolded protein state.

Prions have been held responsible for a number of degenerative brain diseases including: scrapie (a fatal disease of sheep and goats) mad cow disease, Creutzfeldt-Jacob disease, kuru, an unusual form of hereditary dementia known as Gertsmann-Straeussler-Scheinker disease. possibly some cases of Alzheimer's disease.

When a prion enters a healthy organism, it induces existing, properly-folded proteins to convert into the diseaseassociated, prion form. the prion acts as a template to guide the misfolding of more protein into prion form. These newly-formed prions can then go on to convert more proteins themselves; this triggers a chain reaction that produces large amounts of the prion form.

HOW COMMON IS PRION DISEASE?

These disorders are very rare. They affect about one person per million worldwide each year. Approximately 300 cases occur annually in the United States.

WHAT IS PRION DISEASE?

Prion diseases belong to group of progressive conditions that affect the nervous system in humans and animals. In people, prion diseases impair brain function, causing memory changes, personality changes, a decline in intellectual function (dementia), and problems with movement that worsen over time.

SIGNS AND SYMPTOMS:these conditions typically begin in adulthood, and these disorders lead to death within a few months to several years. Familial prion diseases of humans include classic Creutzfeldt-Jakob disease (CJD), GerstmannStrussler-Scheinker syndrome (GSS), and fatal insomnia (FI). These conditions form a spectrum of diseases with overlapping signs and symptoms

All known prions induce the formation of an amyloid fold, in which the protein polymerises into an aggregate consisting of tightly packed beta sheets. Amyloid aggregates are fibrils, growing at their ends, and replicating when breakage causes two growing ends to become four growing ends. The incubation period of prion diseases is determined by the exponential growth rate. Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in variousneurodegenerative diseases.

CHARACTERSTICS OF PRIONS:

This altered structure is extremely stable and accumulates in infected tissue, causing tissue damage and cell death. This structural stability means that prions are resistant to denaturation by chemical and physical agents, making disposal and containment of these particles difficult. Prions come in different strains, each with a slightly different structure, and most of the time, strains breed true. Prion replication is nevertheless subject to occasional epimutationand then natural selection just like other forms of replication.[8] However, the number of possible distinct prion strains is likely far smaller than the number of possible DNA sequences, so evolution takes place within a limited space.

Radiation biologist Tikvah Alper and mathematician John Stanley Griffith developed the hypothesis during the 1960s that some transmissible spongiform encephalopathies are caused by an infectious agent consisting solely of proteins.Their theory was developed to explain the discovery that the mysterious infectious agent causing the diseases scrapie and CreutzfeldtJakob disease resistedionizing radiation. A single ionizing "hit" normally destroys an entire infectious particle, and the dose needed to hit half the particles depends on the size of the particles. The data suggested that the infectious agent was too small to be a virus.

Isoforms:The protein that prions are made of (PrP) is found throughout the body, even in healthy people and animals. However, PrP found in infectious material has a different structure and is resistant to proteases, the enzymes in the body that can normally break down proteins. The normal form of the protein is called PrPC, while the infectious form is called PrPSc the C refers to 'cellular' or 'common' PrP, while the Sc refers to 'scrapie', a prion disease occurring in sheep. While PrPC is structurally well-defined, PrPSc is certainly polydisperse and defined at a relatively poor level. PrP can be induced to fold into other more-or-less well-defined isoforms in vitro, and their relationship to the form(s) that are pathogenic in vivo is not yet clear.

TRANSMISSIBLE SPONGIFORM
ENCEPHALOPATHIES
Animals

Bovine spongiform encephalopathy (BSE) Scrapie in sheep and goats Transmissible mink encephalopathy Chronic wasting disease of deer, elk

Humans

Kuru Creutzfeldt-Jacob disease (CJD) Fatal familial insomnia (FFI) Gerstmann-Straussler syndrome (GSS)
TSEs

are always fatal

First identified with Spongiform encephalopathies Characteristics of infection:

Loss of motor control Dementia Paralysis Encephalitis Widespread neuronal loss

Ways of infection:

Infectious (including diet, after surgical procedures, corneal transplants etc.) Hereditary (autosomal and dominant)

KURU
Animals

Bovine spongiform encephalopathy (BSE) Scrapie in sheep and goats Transmissible mink encephalopathy Chronic wasting disease of deer, elk

Humans

Kuru Creutzfeldt-Jacob disease (CJD) Fatal familial insomnia (FFI) Gerstmann-Straussler syndrome (GSS)
TSEs

are always fatal

SCRAPIE
An

animal model was needed to study TSEs Scrapie disease of sheep had many similarities to kuru in terms of symptomatology and etiology Could be transmitted to hamsters and mice, kuru could not Scrapie was used as first good animal model TSE 2 month incubation in rodents Infectious agent purified 5000 fold Nuclease resistant UV and heat resistant Sensitive to protease (only at high levels) & protein denaturants

Brain Damage from Spongiform Encephalopathy

vacuole

Source: UC Davis School of Veterinary Medicine

TYPES OF TSES
Infectious e.g., kuru, BSE Spread by

(mad cow disease), scrapie

consumption of infected material Iatrogenic spread (organ transplant, esp. cornea) transfusion
Sporadic

1-2 million infected worldwide, late in life Evidence mounting that some sporadic TSE is really result of infection Due to autosomal dominant mutation of PrP Inherited at least 10-15% of total human TSE cases

Familial

Each

of these can be transmitted experimentally

BOVINE SPONGIFORM ENCEPHALOPATHY (BSE)

MAD COW DISEASE

In Britain in the 1970s, hydrocarbon-solvent extraction of meat and bone meal (MBM) for cattle feed was abandoned In 1987, BSE emerged In 1988, BSE became a reportable disease Epidemiology suggested a prion disease, and MBM use was abandoned BSE incubation period is ~5 years Estimated that over 1,000,000 cattle were infected In 1989, human consumption of bovine CNS tissue (thought to have the highest prion concentration) banned based on fears of transmission to humans In 1996, a new type of CJD appeared in Britain and France; young patients (<40 years old) and different neuropathology

EFFECT OF PRIONS ON NEURAL TISSUE

Convert PrPc into PrSc PrSc has identical primary structure but different beta structures leading to resistance of protease cleavage. Brain tissue collects PrSc causing too much protein accumulation. Distinguished by nerve cell death causing large vacuoles and plaques in brain tissue

How do prions function?

PrPc

PrPSc

The prion protein exists in two forms. The normal, innocuous protein (PrPc) can change its shape to a harmful, disease-causing form (PrPSc). The conversion from PrPc to PrPSc then proceeds via a chainreaction. When enough PrPSc proteins have been made they form long filamentous aggregates that gradually damage neuronal tissue. The harmful PrPSc form is very resistant to high temperatures, UVirradiation and strong degradative enzymes.

Criteria for prion demonstration

Transmissible and associated with phenotype Reversible curability from cured individual, phenomenon can arise again because the same event may reoccur in the same genotype Overproduction of normal protein increases frequency of prion formation more normal molecules will be converted to prion form Phenotype relationship of prion and mutation of the normal gene for its protein in the host

Advances in prion control

BSE-resistant cattle
Bovine PrPc gene cloned, modified by site-directed mutagenesis to produce BSE-resistance form Cattle were transformed with modified form of the gene, targeted to replace natural PrPc gene Transgenic animals homozygous for mutant gene express mutant copy and are resistant to BSE, but do not show altered sleep/wake cycles as seen in knockout mice

Depleting neuronal PrPc in prion infection prevents disease and reverses spongiosis
Using transgenic mice, first demonstration that prion infection and pathology can be reversed by ceasing expression of endogenous PrPc copy

Different prions affect different parts of the brain

Cerebral cortex When the cerebral cortex is affected, the symptoms include loss of memory and mental acuity, and sometimes also visual imparement (CJD). Thalamus Damage to the thalamus may result in insomnia (FFI). Cerebellum Damage to the cerebellum results in problems to coordinate body movements and difficulties to walk (kuru, GSS). Brain stem In the mad cow disease (BSE), the brain stem is affected.

Species barrier
Infectous dose between species is usually higher than between animals of the same species (possibly a million fold), but it is sometimes the same (e.g. between scrapie doses for mink) When a species has been infected with a TSE of a different species it can then go on to infect a range of animals that the original species could not, and with a different dose. When a species has been infected, it can infect additional animals of the same species with much lower doses of agent. The histopathology of the disease in an animal infected from another species is not the same as if it had been infected from one of the same species. The incubation period of an animal infected from another species is much longer than that of an animal from one of the same species.

A model for the progression of transmissible spongiform encephalopathy (TSE) pathogenesis.