Lecture 16: Prions

Question 1

Molecular dogma

Answer 1

DNA-RNA-Amino acid chain-protein

Question 2

Prion name

Answer 2

PROteinaceous INfectious Particle

Question 3

What are prions?

Answer 3

Infectious misfolded Prp proteins that cause protein clumping and lead to neurodegeneration
α-helix —> β-pleated sheet

Question 4

Scrapie

Answer 4

First known sign of prions
Degenerative sheep illness

Question 5

Kuru

Answer 5

-Found in the Fore people of Papua New Guinea
-prion illness spread through cannibalism
Discovered by Bill Hadlow and D. Carleton Gajdusek

Question 6

Tikvah Alper

Answer 6

Discovered the scrapie agent does not have nucleic acid. Discovered this by irradiating brain slurry with UV and inoculating mice with brain material. Mice still became infected.

Question 7

Stanley Prusiner

Answer 7

Discovered scrapie was caused by a protein
-won Nobel prize

Question 8

Prp

Answer 8

-Found in all mammals
-encoded in human chromosome 20
-~250 amino acids
Normal protein called cellular Prp or Prpc

Question 9

Prp-c vs. Prp-sc

Answer 9

Prp-c=cellular prion protein
Prp-sc=rouge prion form

Question 10

Prp-sc

Answer 10

Protease resistant
Converts normal Prp-c to rouge form

Question 11

Normal function of Prp

Answer 11

-High expression in central and peripheral nervous system
-Resides extracellularly in lipid rafts where it is attached to glycosyl phosphoinosityl (GPI) anchor
-undergoes endocytosis and cleavage

Question 12

Amyloid plaques

Answer 12

Misfolded, insoluble, protease resistant, fibrous protein aggregates with distinct staining properties

Question 13

Amyloid plaque diseases

Answer 13

-Alzheimer’s—>protein amyloid-β
-Alzheimer’s—>Tau
-Parkinson’s—>α-synuclein
-Amyotrophic lateral sclerosis (ALS)
—>TDP-40

Question 14

Human prion diseases

Answer 14

-Kuru
-Creutzfeldt-Jakob disease
-Fatal Familial Insomnia
-Gerstmann-Sträussler-Scheinker syndrome

Question 15

Different forms of prion disease

Answer 15

•Sporadic-spontaneous conversion
•Acquired-acquired conversion
•Inherited-germline mutation, uncommon
•Sporadic-somatic mutation

Question 16

Creutzfeldt-Jakob disease

Answer 16

•85% of all human prion diseases
•1 in a million people, 350 in US each year
•85% die in 1 year
•mostly ppl 50-70
•Usually presents as psychiatric disorder
•”Relentlessly progressive”

Question 17

Causes of Creutzfeldt-Jakob disease

Answer 17

*Genetic predisposition (10%)
*Iatrogenic (acquired in medical procedure) (iCJD) (<5%)
-Surgery, hormones derived from the brain, electrodes, dural grafts
*vCJD (variant CJD)
-Ingestion of contaminated meat
*Sporadic or classical CJD (85%)

Question 18

Bovine spongiform encephalopathy (Mad cow disease) and vCJD

Answer 18

Total cases: 229 cases of vCJD (most in UK and France)

Question 19

Fatal familial insomnia

Answer 19

•Genetic disease, autosomal dominant (few cases are sporadic)
•40-80 families worldwide
•specific mutations in Prp gene at codon 178
•Hypothalamus function is initial target
•Progressive untreatable insomnia, loss of circadian rhythm, endocrine disorders, motor disorders & dementia

Question 20

Gerstmann-Sträussler-Scheinkler syndrome

Answer 20

•Genetic-autosomal dominant
-sometimes considered a subclass of CJD
•1in 10-100 million people (56 known families)
•average age 35-50
•Survival-5 years after first symptoms
•50% of cases have mutation in Prp codon 102
-often disrupts and removes GPI anchor

Question 21

Variably protease-sensitive prionpathy (VPSPr)

Answer 21

Discovered in 2006
-sporadic
-Codon 129

Question 22

Why are there different forms of prion diseases?

Answer 22

•Different mutations within Prp will convert the normal conformation into unique structural forms of Prp-sc
•Initiated in different locations on the brain

Question 23

Chronic wasting disease

Answer 23

•Harbored in 10%-80% of deer nationwide
•Origin uncertain
•Highly contagious (no evidence for human transmission)
•Spread direct and indirectly
-Feces, body fluids, aerosols

Question 24

Treatment

Answer 24

•Universally fatal and “relentlessly progressive”
•No treatment
-Some drugs use to alleviate symptoms

Question 25

Diagnosis

Answer 25

•Definitive diagnosis-Autopsy and histological analysis of the brain
•No promoted diagnostic test, but several tests can help build a diagnosis:
-Clinical presentation & family history
-Electroencephalography (EEG)
-Cerebrospinal fluid-based tests
-Brain biopsy
-MRI
-Present Prp-sc in peripheral lymphoid tissue

Question 26

Prions in the fungi kingdom

Answer 26

Prions are widespread in the fungi kingdom, but these proteins are able to switch protein shape back and forth
•Heterokayton incompatibility (Het-s)
•Nitrogen catabolism (Ure2)
•Translation termination (Sup35)