• proteinacious infectious organisms
• infectious agent = abnormal protein
  • not really an organisms
  • accumulates in neurons and cause progressive neurodegenerative disorders
• transmissible
• unique prion disease found in multiple animal species

• normal protein (PrP^c) undergoes a confirmational change to abnormal form (PrP^Sc)
• accumulation of pathogenic isoform in neurons causes disease
  • form beta pleated sheets, rods, fibrils
  • lead to neurological symptoms
• histopathology
  • spongiform degeneration
  • vacuoles within and surrounding cells
  • transmissible spongiform encephalopathies (TSE) aka another name for prion diseases

• encoded on PNRP gene on chrom 20 (single copy)
• highest level of expression in neurons and other CNS cells
  • also in lymphocytes, skel/cardiac muscle cells
• polymorphic at residue 129 (Val to Met)
  • homozygous for Met assoicated with prion disease
• anchored to cell surface by GPI anchor
• function unknown (may be involved in cell signaling or neuronal development)

• nucleated polymerization
  • the two protein forms are normally in equilibrium where c form heavily predomninates Sc form
  • highly ordered aggregates of PrP^Sc recruit monomeric PrP^C into the aggregate
    • only aggregate form is transmissable
• template assistance
  • small number of PrP^C and PrP^Sc oligomerize, possible along with a molecular chaperone
  • PrP^Sc then acts as catalyst or template to convert PrP^C

• PrP^C cycles between cell surface and endosomes
• conversion to PrP^Sc may occur along this route
• PrP^Sc accumulates in vacuoles

• resistant to:
  • most proteinases (except proteinase K)
  • inactivators of viruses
  • inactivators of nucleic acid
  • heat at 80 C
  • drying
  • ionizing radiation
• sensitive to:
  • proteinase K
  • protein denaturing agents
  • organic solvents
  • detergents
  • sodium hypochlorite

Also highly insoluble, predominantly found in vacuoles, and secondary structure is made predominantly of beta sheets

• predominantly alpha helix
• cellular location- cell surface
• normally seen in brain
• very soluble

• different strains are differential based on fragment patterns after proteinase K digestion
• vary with respect to AA sequence and tertiary structure
• variability in strains have been assoicated with different clinical presentations

• interference with ubiquitin proteosome pathway
  • normally degrades abnormal proteins
  • protect against against neurodegenerative disease
  • blockade of pathway leads to loss of critical cellular function (eventually induce apoptosis)
• loss of normal PrP^C function
• toxicity of accumulated PrP^Sc

• end result is same in all prion diseases
  • accumulation of PrP^Sc intracellularly
  • spongiform vacuolation
  • formation of amyloid plaques
  • neuronal cell loss
  • microglial activation and proliferation of astrocytes
• produces no:
  • significant immune response
  • inflammation
  • IFN/cytokine prod.

• no foreign Ag
• no nucleic acid
• no immune response to prion
• species barrier: most TSE not transmissible between species
  • except BSE
• stable against multiple chemical and physical insults
  • heat
  • UV radiation
  • nucleases

• familial prion disease
• sporadic CJD (most common prion disease)
• iatrogenic CJD
• acquired CJD
  • kuru
  • variant CJD

• long incubation period (yrs)
• chronic, progressive neurological disease
• fatal outcome
• pathology limited to CNS
• experiementally transmissible

• genetics
  • autosomal dominant, variable penetrance
  • inherited mutations of PNRP gene (specific mutation related to phenotype)
• types
  • familial CJD
    • Glu to Lys substitution at residue 200
    • earlier age of onset and longer course than sCJD
  • Gerstmann Straussler Scheinker disease- cerebellar ataxia
  • familial fatal insomnia- homozygous for Met at residue 129

• no germ line mutation in PRNP gene
• age of onset- 60 yrs old
• common init. symptoms
  • fatigue, disordered sleep
  • behavioral changes
  • visual loss, cerebellar ataxia, aphasia, oir motor deficits
  • rapid progression- prominent cognitive decline/dementia
  • develop myoclonus
• death in 4-5 mnths

• random misfold of PrP^C
• somatic mutation in PRNP gene

• consumption of contaminated foods (contain CNS, spinal cord, bone marrow, meats)
  • animal by products used in animal feed
  • ritual cannibalism of dead family members
  • ingest contaminated beef
• processed organ tissues (hormones such as hGH)
• neurosurgery (contaminated instruments)
• blood transfusions

• eastern highlands of Papua New Guinea in 1950s
• disease center in South Fore tribe
• ritual mortuary cannibalism of dead family members
  • outbreak likely originated by canabalism of individual with sCJD
• incidence decreased after cessation of cannibalism

• means "shivering"
  • initially presents with tremors, ataxia, postural instability
  • long incuation period
  • fatal over 2 months-2 yrs
• primarily cerebellar involvement
  • many with amyloid plaques on brain
• if had homozygous PRNP on codon 129, associated with earlier age of onset and higher sik of disease

• scrapie (sheep, goats)
• BSE (cows)
• chronic wasting disease (elk, deer)
• transmissible mink encephalopathy

• in sheep goats, but not transmissible to humans
• neurogenerative disease
  • sheep scrape their coats against rocks
  • excessive lip smacking, hopping gait, seizures
• similar neuropathology to human prion disease

• deer, elk
• present in heards of at least 14 states and 2 canadian provinces
• spread within deer heards
  • possible blood or salivary transmission
• no evidence of transmission in nondeer/elk

• etiologies
  • cattle feed contaminated with scrapie infected sheep products
  • cattle feed contaminated with sporadic TSE infected cow products
• mean incubation- 5 yrs
• transmissible to humans: called vCJD

• PrP^Sc in lymphoid tissue
• likely due to ingestion of meat from animals with BSE

• younger individuals
• prsent with psyc/behavioral findings
• not as rapid as decline as sCJD
• all have Met homozygosity at codon 129 of PRNP

• HGH (from cadavers)
• dural grafts
• corneal transplants
• organ transplants (liver)
• contaminated neurosurgical instruments
• homozygosity at codon 139 of PRNP gene increase susceptibility

• sCJD
  • pulvinar sign absent
  • not in lymphoid tissue
  • sharp EEG waves
• vCJD
  • absent EEG sharp waves
  • present in lymphoid tissue
  • pulvinar signs on MRI present in most cases

• use disposable instruments whenever possible
• label specimens carefully, notify lab
• effective deconatmination
  • steam autoclaving at 121-132 C
  • NaOH
  • chlorine greater than 10,000 ppm
  • guanidine thiocyanide
  • Na hypochlorate (30-60 minutes for inanimate surfaces)

• EEG
• CSF examination
  • see 14-3-3 protein: surrogate marker for neuronal injury
• MRI (pulvinar sign)
• tissue biopsy
  • brain for all prion disease
  • lymphoid tissue: vCJD
  • muscle: sCJD
  • immunocytochemical staining for PrP
  • Western Blot analysis

• florid plaques consist of amyloid core surrouned by ring of vacuoles
• spongiform degeneration and reactive astrocytes
• immunostaining of pathological prion protien: pretreated to denature normal PrP and staining with Prp Ab reveals plaques staining for PrP^Sc

• no specific tx proven effective
• experimental
  • anti PrP Ab
    • Fabs bind FrP^C/FrP^Sc to prevent prion propagation
    • PrP^Sc disappears from infected neuroblastoma cells
    • hasnt been tested in humans
  • quinacrine (TCA)
    • clearance of PrP^Sc from infected cells in vitro
    • in clinical trials