Lecture 16: Prions Flashcards
(26 cards)
Molecular dogma
DNA-RNA-Amino acid chain-protein
Prion name
PROteinaceous INfectious Particle
What are prions?
Infectious misfolded Prp proteins that cause protein clumping and lead to neurodegeneration
α-helix —> β-pleated sheet
Scrapie
First known sign of prions
Degenerative sheep illness
Kuru
-Found in the Fore people of Papua New Guinea
-prion illness spread through cannibalism
Discovered by Bill Hadlow and D. Carleton Gajdusek
Tikvah Alper
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.
Stanley Prusiner
Discovered scrapie was caused by a protein
-won Nobel prize
Prp
-Found in all mammals
-encoded in human chromosome 20
-~250 amino acids
Normal protein called cellular Prp or Prpc
Prp-c vs. Prp-sc
Prp-c=cellular prion protein
Prp-sc=rouge prion form
Prp-sc
Protease resistant
Converts normal Prp-c to rouge form
Normal function of Prp
-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
Amyloid plaques
Misfolded, insoluble, protease resistant, fibrous protein aggregates with distinct staining properties
Amyloid plaque diseases
-Alzheimer’s—>protein amyloid-β
-Alzheimer’s—>Tau
-Parkinson’s—>α-synuclein
-Amyotrophic lateral sclerosis (ALS)
—>TDP-40
Human prion diseases
-Kuru
-Creutzfeldt-Jakob disease
-Fatal Familial Insomnia
-Gerstmann-Sträussler-Scheinker syndrome
Different forms of prion disease
•Sporadic-spontaneous conversion
•Acquired-acquired conversion
•Inherited-germline mutation, uncommon
•Sporadic-somatic mutation
Creutzfeldt-Jakob disease
•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”
Causes of Creutzfeldt-Jakob disease
*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%)
Bovine spongiform encephalopathy (Mad cow disease) and vCJD
Total cases: 229 cases of vCJD (most in UK and France)
Fatal familial insomnia
•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
Gerstmann-Sträussler-Scheinkler syndrome
•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
Variably protease-sensitive prionpathy (VPSPr)
Discovered in 2006
-sporadic
-Codon 129
Why are there different forms of prion diseases?
•Different mutations within Prp will convert the normal conformation into unique structural forms of Prp-sc
•Initiated in different locations on the brain
Chronic wasting disease
•Harbored in 10%-80% of deer nationwide
•Origin uncertain
•Highly contagious (no evidence for human transmission)
•Spread direct and indirectly
-Feces, body fluids, aerosols
Treatment
•Universally fatal and “relentlessly progressive”
•No treatment
-Some drugs use to alleviate symptoms
