prions

nature of prion infectious agent

-can be transmitted -can replicate -cause variable disease -they have arisen in organisms during evolution -they are able to propagate themselves and the diseases they cause

Mad Cow disease or bovine spongiform encephalopathy origin hypothesis

-spontaneous PrPc mutation -mutated scrapie prion

prp encoded by host genome

-uninfected cells express PrPsc: a cellular isoform -expressed on surface neurons, lymphocytes, follicular dendritic cells -normal function unknown -knockout mice remain healthy -binds copper ions -presumed to function in transmembrane transport or signaling

PrPC involved in secretory pathway of cells steps:

1. PrPc synthesized on rough ER 2. PrPc moves to plasma membrane via Golgi secretory pathway to bind Cu++ 3. PrPc cycled from the membrane into endocytic vesicles 4. PrPc is either degraded or moves back to cell surface to bind Cu++ 5. Conversion (folding) of PrPc to PrPcos accumulated of fibrils

how many known mutations in PrPsc are associated with prion disease?

20

PrPc contains how may alpha helices?

3

Prion diseases may have much in common with

Alzheimers and Parkinsons

prion protein name

Pr

scrapie protein name

PrPsc

Diseases caused by aggregation of proteins into fibers known as amyloid include

Type II diabetes Alzheimer's Parkinson's Huntingtion's disease

the infectivity of prions is resistant to

UV and ionizing radiation-damage nucleic acid -infectivity sensitive to phenol and SDS-denature protein -therefore protein and not nucleic acid

human prions are encoded by

a host gene

PrPsc is not crystallized but contains less ___ helices and more ___ strands- significant conformational change

alpha; beta

affected areas contain microscopic insoluble _______ __________ and macrocrystalline arrays known as amyloid plaques

amyloid fibrils

Humans who are homozygous for valine at position 129 are predisposed for

both acquired and sporadic CJD

prion disease are not usually transmitted among different species but

bovine spongiform encephalopathy developed in Britain and apparently spread to humans

prion diseases in animals

bovine spongiform encephalopathy, chronic wasting disease, exotic ungulate encephalopathy, feline spongiform encephalopathy, scrapie, transmissible mink encephalopathy

how is PrPc encodes?

by a single exon of a unique gene

prion disease

chronic, progressive, invariably fatal central nervous system degeneration

GSS families have

common double mutation at aa 178 and 200

PrPc + proteinase K

complete digestion

what kind of animal is infected by chronic wasting disease

deer elk

Characteristics of Creutzfeldt Jakob Disease

dementia and ataxia-fatal within a few months of symptoms

prions have proteins but no

detectable nucleic acid

what kind of animal is infected by exotic ungulate encephalopathy

domestic and wild cats

All victims of vCJD are

homozygous for methionine at 129

Where were prion disease first detected?

in domestic ruminants

inoculation of brain tissues in experiment with prions

kuru and cjd ---> chimps scrapie ---> mice and hamsters -transmission of disease

prion disease in humans

kuru, creutzfeldt jakob disease, variant cjd, fatal familial insomnia, gerstmann-straussler syndrome

Gerstmann Straussler Syndrome

lack of muscle coordination, difficulty speaking and decline in cognitive ability. It is an inherited disease

spongiform encephalopathy

large vacuoles in the cortex and cerebellum

Bovine spongiform encephalopathy

mad cow disease

MBM was

made into a high protein supplement and fed to cattle sheep pigs and spread BSE in feed

the prion hypothesis proposes that

misfolded forms of a cellular protein can catalyze the refolding of properly folded native protein molecules into similarly misfolded conformations

purified 27-30 kd protein

not detected in uninfected brain tissue

rendering definition

process to separate protein and fat from waste tissue

characteristics of kuru

progressive ataxia leading to total incapacitation-fatal within 6-12 months. -Fore tribe in Papa New Guinea -Epidemic developed in 1940-1950 -ritualistic cannabilism- eating brain of deceased family member as sign of respect and mourning -forbidden by Australian government in 1950s and stopped by 1960 -incubation 5-20 years

prion hypothesis

proposes the infectious agent that transmits TSE is PrPsc -PrPsc is a seed that induces the formation of more of itself -the seed may arise spontaneously or by infection with PrPsc -mutations in the PrP make formation of the seed more probable -transmission of ingested seed to the brain might require ''replication'' of the agent in lymph nodes

suggests heterozygosity at position 129

protects against both inherited and infectious prion disease

Prusiner 1982:

proteinaceous infectious particle "prion" (Pr) -nobel prize 1997

what are prions?

proteinaceous infectious particles -new kind of infectious agent that transmits prion disease -small filterable infectious particles that contain single species of protein called PrP (prion associated protein) -replicates itself without nucleic acid -no sign of immune response

Variant Creutzfeldt Jakob Disease

psychiatric symptoms usually depression-fatal within 12-14 months after signs appear -eating beef from cow with BSE

what is MBM (meat and bone meal)

rendering of waste parts of mixed species including sheep and cattle not suitable for human consumption

PrPsc + proteinase K

resistant 27-30-KDa core (retains infectivity)

what is scrapie

scrapie in sheep and goats in marked by behavioral changes, tremor, and uncoordinated movements that progress to death -known in Britain for hundreds of years -endemic in the UK- affects 0.5-1% of sheep population/year

what kind of animal is infected by scrapie

sheep/goat

brain pathology is ____________ __________________ -large vacuoles in cortex and cerebellum give brain sponge like appearance

spongiform encephalopathy

CNS tissue from animals with scrapie reveal

spongiform encephalopathy-large vacuoles in the cortex and cerebellum (brains look like sponge) -no signs of brain inflammation -behaves like infectious disease

the existence of prions suggest

that information coded in the three dimensional structure of a protein can be transferred from organism to organism and propagate itself without the intervention of nucleic acid

PrPc and PrPsc require

the same amino acid sequence

Fatal Familial Insomia characteristics

untreatable complete sleeplessness. Fatal within a year and a half. It is usually inherited but sporadic cases have been reported

symptoms of _______ occurs much earlier in life than ______. It is thought to be contracted by consumption of beef from cattle infected with BSE

vCJD; sCJD

Most victims of Kuru;

were homozygous at position 129

can infectious agents exist without genomes?

yes