BIOL 0510 - Prions

What is the primary structure of proteins?

a sequence of amino acids in a chain

What is the secondary structure of proteins?

alpha helices or beta pleated sheets formed by hydrogen bonds within the amino acids linking

What is the tertiary structure of proteins?

structure formed by interactions between alpha helices and pleated sheets like disulphide bonds and ionic bonds

What is the quaternary structure of proteins?

a protein consisting of more than one amino acid chain

What determines the function of a protein?

its shape

What are prions extremely resistant to?

heat, chemicals and decomposition

What makes prions so resistant?

lack of nucleic acid and the protein form they take

What are prion diseases a consequence of?

the accumulation of PrP^Sc which is an isomer of the normal PrP^C

Prion diseases can be…

infectious, genetic or sporadic

Describe the size of prions?

100x smaller than the smallest virus

What makes prions different from all other known infectious pathogens?

they are the only ones without nucleic acid

What is PrP^Sc?

misfolded PrP^C resulting in protein aggregation and clumping that leads to neurodegeneration of the central nervous system

What is the significance of Sc?

Scrapie which was first reported in Europe in the early 18th century in sheep

During the mid 1800s, what was noticed about the brain of sheep with scrapie?

holes in the brain tissue which is called brain vacuolation

When was scrapie first transmitted successfully?

1939

How was scrapie first transmitted successfully?

by intraocular inoculation of brain or spinal cord tissue from an affected animal

How long did it take for the disease to develop?

1-2 years so previous experiments may have failed because researchers didn’t wait long enough

What caused the large outbreak of Scrapie in 1939?

sheep vaccination against looping illness. (Vaccine prepared from formaldehyde-treated sheep brain extract)

What symptoms were associated with Kuru?

inability to walk and eat, shivering and most common in children and women

What did Gajdusek notice when he took tissue samples for people with Kuru?

brain vacuolation which he attributed to their cultural practice of cannibalism

What did Bill Hadlow do?

recognised that Kuru resembled Scrapie

What were the results of Gajdusek’s experiment with chimpanzees?

after being infected with the brain tissue of people who had Kuru, it took 18-21 months for the disease to develop

What were the hypotheses about what causes kuru?

a slow unconventional virus or a slowly progressive microbial infection

What did Tikvah Alper do?

conducted experiments with the agent of Scrapie and showed that there’s no dose of radiation that can make it inactive. Therefore, there’s no nucleic acid

What did Stanley Prusiner do?

treated the brain homogenate with DNAses and RNAses and other agents. He found that it was completely resistant. The protein fraction was found to be the infectious agent and he called it PrP

What is PrP?

a protein found in all mammals that is around 250 amino acids long

What happens when Prp^C comes in contact with PrP^Sc?

the 3D conformation is altered to the disease form

What do all prion diseases cause?

Transmissible Spongiform Encephalopathy (TSE) in mammals

What pathology is associated with TSE?

brain vacuolation, apoptosis of neurons, astrogliosis and the accumulation of PrP^Sc

Why is it encephalopathy and not encephalitis?

there’s no inflammation or antibody response

Where is normal PrP expressed?

in a variety of organs and tissues

Where is normal PrP highly expressed?

in the central and peripheral nervous systems

Where does PrP reside?

extracellularly in lipid rafts, where it is attached to a (GPI) anchor

What is the normal function of normal PrP?

we aren’t sure as knockout mice show unclear function

What happened to PrP knockout mice?

they became resistant TSE

What can we conclude from the studies on knockout mice?

rodents demonstrate that oral infection with prions can occur, but is inefficient compared to intracerebral inoculation

What happens to mice with a P120L mutation?

they develop TSE

What did Dr Allison Krauss find?

using Cryo-EM, she found that in prion disease, the rogue form of PrP stacks on top of each

Why is it hard to know if a person has a prion disease?

prions can spread silently across a person’s brain for years before symptoms arise

What happens as the concentration of Prp^Sc increases in the brain?

the rate of conversion for normal Prp increases

When does someone with a prion disease begin to experience a rapid decline?

once prions start to kill neurons and symptoms occur

What are amyloids?

misfolded, insoluble, protease resistant protein aggregates that have distinct staining properties

How many neurodegenerative diseases are caused by amyloids?

over 20

Are some proteins more likely to misfold than others?

yes, they are known as amyloidogenicproteins

PrP can also cause…

amyloid plaques

Can amyloid plaques be caused by different protein aggregates?

Yes for example Tau or Amyloid-beta in Alzheimer’s disease

What makes something a prion disease?

the involvement of PrP

Which type of diseases can both result in amyloid plaques?

prion diseases and neurodegenerative diseases

Are neurodegenerative diseases prion diseases?

no

What are similarities between neurodegenerative diseases and prion diseases?

they mostly affect older people and are fatal

Can prion diseases be sporadic?

yes

How can prion disease be acquired?

contamination from a brain surgery or digestion of brain tissue with rogue PrP

How can prion diseases be genetic?

due to SNPs which make it more likely for PrP to switch to the rogue form overnight

Which disease makes up 85% of all human prion diseases?

Creutzfeldt-Jakob disease

How does Creutzfeldt-Jakob disease usually present itself?

anxiety, depression, withdrawal, delusions and behavioural changes

When was CJD discovered?

1920s in Austria and Germany

10% of CJD are due to…

genetic predisposition

Less than 5% of CJD cases are iatrogenic which is due to…

surgery, hormones derived directly from the brain like human growth hormone, electrodes and dural grafts

Most cases of CJD are…

sporadic

Variant CJD is due to…

contaminated meat

How does variant CJD differ from classical?

happens earlier on in life and it doesn’t kill as quickly

What is the official name of mad cow disease?

bovine spongiform encephalopathy

What did BSE cases lead to?

the ban on ruminants in cattle feed

What was the effect of BSE?

cases of vCJD connected to the ingestion of contaminated meat

What did the experimental studies of those vCJD cases show?

orally ingested prions are absorbed through the intestine into the blood, transported to lymphoid organs and accumulate before being transported to the brain by the peripheral nerves

What is unique about BSE?

it can transfer to lots of different species

What causes fatal familial insomnia?

autosomal dominant mutation in the Prp gene at codon 178

Which area of the brain is targeted by fatal familial insomnia?

the hypothalamus

What is the effect of fatal familial insomnia?

progressive untreatable insomnia, motor disorders, loss of circadian rhythm, endocrine disorders and dementia

What is Gerstmann-Sträussler-Scheinker Syndrome?

an autosomal dominant prion disease

What mutation is associated with GSS syndrome?

a mutation in PrP codon 102 which often disrupts and removes the GPI anchor

What new prion disease was discovered in 2006?

variably protease sensitive prionopathy which is sporadic

What codon is associated with variably protease sensitive prionopathy?

codon 129

What’s one reason why there are different forms of prion diseases?

different mutations result in different structural formations of PrP^Sc. These distinct shapes lead to unique clinical outcomes

What’s another reason why there are different forms of prion diseases?

it can be initiated in different locations of the brain which causes different symptoms

What do people with prion diseases receive?

drugs to alleviate symptoms such as antidepressants

What provides a definitive diagnosis of a prion disease?

a histological analysis of the brain and an autopsy but there’s no premortem diagnostic test

What tests can be used to help build a diagnosis?

MRI, brain biopsy, clinical presentation, family history, EEG and testing for the presence of PrP^Sc in peripheral lymphoid tissue

What is chronic wasting disease?

a highly contagious prion disease that effects deer and elk

How does chronic wasting disease spread?

directly and indirectly through bodily fluids, feces and aerosols

What are fungi able to do with prions?

switch the proteins back and forth between different shapes for different functions