04: TSEs Pt 1

Characteristic of TSE/prion diseases

• Neurodegenerative

• Progressive

• Terminal

Why is it hard to identify TSEs

Prolonged incubation period, often has non-specific CS

Types of TSE transmission

• Infectious

• Spontaneous: atypical variants

• Hereditary

Type of livestock predisposed to TSEs

Black faced sheep

Prion

Infectious protein

PrP

The protein coded by the prion gene

Prion gene

PRNP

PrP^C

Cellular prion protein- not misfolded or infectious, but is the normal variant

PrP^D

Disease associated prion protein

Cellular location of PrP^C

PM or inside endosomes

Molecule that anchors PrP^C to the PM

GPI

Characteristic of PrP^C c-terminus

Alpha helices

Types of cells with PrP^C

• CNS cells

• Lymphocytes

• Endothelial cells

T/F: PrP^C is soluble

True

T/F: PrP^C is susceptible to proteolysis

True

Characteristic of PrP^D c-terminus

Lots of beta pleated sheets

T/F: PrP^D is soluble

False

T/F: PrP^D is susceptible to proteolysis

False

How does an animal end up with lots of PrP^D

It catalyzes the misfolding of PrP^C

Hallmarks of the “protein-only hypothesis”

• PrP^D causes TSEs

• There is a genetic predisposition and unknown protein cofactors

• PrP^D is self perpetuating

• PrP^D is infectious and transmissible

General clinical signs of TSEs

• Intense pruritis

• Excitation

• Seizures

• Ataxia

• Incoordination

• Blindness

• Emaciation

• Paralysis

Why are TSEs a pain for anatomic pathologists (and anyone trying to diagnose)

No gross lesions

Best diagnostics for TSEs

• Histopathology

• Immunohistochemistry

• ± Western blot

Changes observed in histopath samples with TSE

• Spongiform change in neuropil: discrete, rounded vacuoles

• Neuronal vacuolation

• Astrogliosis: hypertrophy and hyperplasia

• Amyloid plaques

How does IHC work

Incubates formalin fixed tissue in a primary antibody with a binding region that recognizes the TSE epitope, then incubates that with a secondary antibody bound to a recorder molecule, then exposes the sample to the substrate to visualize any PrP^D present

Monoclonal antibody

Lab synthesized antibody that only recognizes one epitope

Polyclonal antibody

In vivo synthesized antibody that recognizes multiple epitopes

Patient demographic for BSE

Young adult (3-6 years)

Types of BSE

Classical (C type) and Atypical (H type or L type)

CS indicative of BSE

None; CS are non-specific

Site of C type PrP^BSE accumulation

Obex of brain stem, specifically the dorsal vagal nucleus, and spinal cord

Histopath signs associated with C type BSE

Lots of neuropil and neuronal vacuolation

Site of atypical PrP^BSE accumulation

Thalamus and olfactory bulbs

Histopath signs associated with atypical BSE

Lots of amyloid plaques

Human disease caused by PrP^BSE

Creutzfeldt Jakob Disease (CJD)

Transmission of BSE as CJD

Ingestion of contaminated meat or blood transfusions

Signs of CWD in deer

Hypersalivation and broad stance

CS indicative of CWD

None; CS are non-specific

Site of PrP^CWD accumulation

Olfactory tubercle, cerebral cortex, and lymphoreticular tissues (retropharyngeal LN, GALT, other LNs)

Histopath signs associated with PrP^CWD

Neuropil and neuronal vacuolation, amyloid plaques (like a combo of both BSE types)

Human disease caused by PrP^CWD

None, not zoonotic