BIOL0510: Prions

What are prions? Define them and explain what they are

name: proteinaceous infectious particles (PrP)

what: Prp are misfolded, resulting in protein aggregation/clumping that leads to neurodegeneration of the CNS

What are the 4 major properties of prions?

1. don’t have nucleic acids

   • they’re only proteins

2. resistant to heat, chemicals, and decomposition

3. can cause infectious, genetic, or sporadic disorders

4. disease results from the accumulation of PrPsc protein (infectious isomer of normal PrPC)

What are TSEs?

transmissible spongiform encephalopathy: infectious diseases (T) leading to brain vacuolation, aka holes, (S) and a lack of immune response (E)

What makes TSEs and other neurodegenerative diseases similar?

they both are characterized by disease-causing plaques in the brain

What makes TSEs different from other neurodegenerative diseases?

TSEs

• are infectious

• caused by prions

Other diseases

• non-infectious

• caused by unique proteins

What causes Alzheimer’s, Parkinson’s, and Amyotrophic lateral sclerosis (ALS)?

Alzheimer’s: amyloid beta and tau misfolding

Parkinson’s: alpha-synuclein

Amyotrophic lateral sclerosis: TDP-40

Explain what makes neurodegenerative diseases distinct from each other

• different proteins/mutations arise

• leads to different protein misfolding, affecting different areas of the brain

• different symptoms manifest

Summarize Scrapie (what, organism, route of infection, discovery, symptoms)

what: the first discovered prion disease

organism: sheep

route of infection: N/A

discovery: 1750s

symptoms: scraping, bite their feet and legs, eventually die, brain vacuolation (holes)

How did scientists in 1939 test and transmit scrapie?

experimentation: inoculated brain or spinal cord tissue from an affected sheep into 2 healthy sheep

result: sheep developed scrapie 1-2 years after inoculation

What caused the scrapie outbreak in 1939? How was it treated?

a vaccination against looping illness

treatment: formaldehyde (but it wasn’t strong enough to kill the prions)

Summarize Kuru (what, organism, route of infection, discovery, symptoms, survival)

what: Fore tribe disease common among women and children

organism: humans

route of infection: cannibalism (eating brain and spinal cord tissue)

• acquired prions

discovery: 1950s

symptoms: shivers, ataxia, weight loss

survival: 9-24 months

What did Gajdusek do?

1. noticed cannibalism in Fore tribe, brain vacuolation in dead members

2. infected chimpanzees with Kuru and waited for them to die around 20-24 months later

   • proved prions were infectious

What did Hadlow do?

the vet that made the connection between brain vacuolation in Kuru and Scrapie

What did Alper do?

the radiologist who proved that prion disease lacks nuclei acids by showing that scrapie was not sensitive to UV radiation (everything with DNA is sensitive to UV)

What 2 things did Pruisner do and how?

1. showed how resilient prions are

   • how: added DNAse, RNAse, viral inactivators, and proteases to brain slurry samples —> inoculated mice —> disease still occurred

2. won Nobel for discovering and purifying PrPsc protein

What is Prp? (length, parts, linkage, location)

• 250 amino acids

• 2 parts: Prp/PrpC

• linked via GPI anchor to outside of membrane

• found in all mammals (on human Chr 20)

What is the normal function of cellular prion protein? (PrpC)

• expressed in a variety of organs and tissues

• high expression levels in the CNS and PNS

• resides extracellularly in lipid rafts, where it is attached to a glycosyl phosphoinosityl anchor (GPI)

• undergoes endocytosis and cleavage

• knockout mice show unclear function

What type of infection are prion infections considered?

SLOW; unconventional agents

What is the prion theory?

prions spread silently across a person’s brain for years without causing any symptoms

• the conversion of PrP to PrPsc increases

• prions aren’t destroyed by the cell; they accumulate, eventually causing cell death

• prions move on to another neuron to begin the cycle again

• once PrPsc concentration is high enough, noticable symptoms strike, and the patient rapidly declines

Describe the timeline of prion disease (5 steps)

1. prions form (3 ways)

2. prion recruitment: prion infects other PrPc to make more prions

3. amyloid plaques form: prion aggregates, creating amyloid fibers —> amyloid plaques

4. neurons are killed (brain holes form): amyloid plaques destroy neurons, creating holes in the brain (vacuolation)

5. clinical symptoms present: anxiety, dementia, loss of motor function

What are the 3 methods for forming prions? Categorize the 7 human prion diseases respectively

1. spontaneous/idiopathic: folding issues arise overtime

   • ex. classical CJD, VPSPr

2. acquired: prion acquired from other organism’s tissues

   • ex. Kuru, vCJD

3. genetic/familial: genetic mutation increases likelihood of misfolding

   • ex. Fatal Familial Insomnia, (genetic)CJD, GSS

What are amyloid plaques?

misfolded, insoluble, protease-resistant protein aggregates w/ distinct staining properties

• cause over 20 neurodegenerative diseases

• some proteins have greater potential to misfold

What proteins are most likely to aggregate for each popular neurodegenerative diseases?

the amyloids for each disease also aggregate in different areas in the brain, perhaps explaining the different initial symptoms associated with each disease (ex. parkinson’s = motor problems, alzheimer’s = memory loss)

What are the 5 human prion diseases we are studying?

1. Kuru

2. Creutzfeldt-Jakob disease

3. Fatal Familial Insomnia

4. Gerstmann-Straussler-Scheinker syndrome

5. VPSPr

Why are there different forms of prion diseases?

different mutations within Prp will convert the normal conformation into unique structural forms of PrpSC, initiated in different locations in the brain

Summarize Classical Creutzfeldt-Jakob Disease (what, organism, route of infection, discovery, symptoms, survival)

what: most common prion disease

organism: humans

• route of infection:

  • sporadic/idiopathic

  • genetic predisposition

  • eating beef with mad cow disease (vCJD: 20-30 y/o’s, 8-38 month survivial)

  • iatrogenic (hospital acquired via brain surgery tools)

  discovery: 1920, Austria

  symptoms:

  • classical: dementia

  • variant: pyschological

  • both: anxiety/depression, dementia, ataxia, coma

  survival: 4 months

What are the three major differences in classical versus variant CJD?

1. duration

2. age range

3. main symptoms

Summarize fatal familial insomnia (organism, route of infection, symptoms, survival time)

organism: humans

route of infection: genetic (codon 178 mutation)

symptoms: plaques form in the hypothalamus, affects circadian rhythm, deadly insomnia

survival time: 18 months

Summarize Gerstmann-Straussler-Sheinker Syndrome (GSS) (what, organism, route of infection, symptoms, and survivial)

what: subclass of CJD

organism: humans

route of infection: genetic, autosomal dominant (a single copy of this mutation on an autosomal chromosome will cause GSS)

• 50% of patients have codon 102 mutation

  • disrupts and removes GPI anchor

symptoms: motor issues, anxiety, dementia

survival: 5 years

Summarize variably protease-sensitive prionopathy (VPSPr) (what, organism, route of infection, discovery)

what: newly discovered prion disease

organism: humans

route of infection: sporadic OR somatic (body cell) mutation in codon 129

discovery: 2006

What are the animal prion diseases we discussed?

1. scrapie

2. chronic wasting disease

3. Bovine spongiform encephalopathy (mad cow disease)

Summarize Bovine Spongiform Encepalopathy (BSE) (what, organism, route of infection, discovery, symptoms)

what: TSE in cows

organism: cows

route of infection: cow feed

• acquired

discovery: 1980s

symptoms: nervousness, aggression; eventually inability to stand

What did farmers do that unintentionally spread BSE and, eventually, vCJD?

• added ruminants (brain material) to cow feed

• cows to develop Mad cow disease

• people that ate the cows developed vCJD years later

Summarize chronic wasting disease (organism, route of infection, discovery, symptoms)

organism: deer

route of infection: feces, body fluids, aerosols

• acquired (HIGHLY CONTAGIOUS and COMMON)

discovery: 1967

symptoms: motor issues, weight loss

How are prion diseases diagnosed definitively? What is observed?

1. from looking directly at brain tissue post-mortem

• observation: brain vacuolation

List 6 ways non-definitive prion disease diagnoses made, and the catch-22 associated with each

1. clinical presentation of familial history (most common)

2. EEG (changes in brain activity)

3. cerebrospinal fluid tests (shake samples to amplify prions)

4. brain biopsy (MIGHT catch a prion)

5. MRI (only certain diseases show up)

6. peripheral lymphoid tissue sample (look for PrPsc, somtimes works)

What makes fungi prions special?

contain proteins that can readily change conformation based on the organism’s needs/environment

What 2 characteristics are associated with fungal prions?

• widespread (many fungi have them)

• they’re non-pathogenic to fungi, yet are still infectious

  • at least 1 conformation is self-propagating (flips other proteins)