Prions

Missense Mutation

Event where different amino acid is encoded in primary protein structure

Normally Folded Cellular Prion Proteins (PrPc)

Normally existing host protein, highly conserved across mammals

Alpha-helical, nervous, immune

PrPCs

• Membrane anchored __ __ (alpha helix/beta sheet) conformation

• Found in __ and __ cells at high amounts

Abnormally Folded Prion Proteins (PrPSc)

Pathological post-translational modifications in folding

Scary, beta sheets, proteases, stable

PrPScs

• “__” prion protein isoform

• PrPSc more than 50% of __ __ (alpha helix/beta sheet)

• Resistance to__ (enzymes)

• Very environmentally __

Transmissible Spongiform Encephalopathies

Aka prion disease

Sporadic transmission, autosomal dominant

__ __ occurs spontaneously due to specific mutations in prion gene

In genetic transmission, this follows a __ __ inheritance

(for TSEs)

Individuals, species, vacuoles, brain

TSEs

• Transmissible: cell-to-cell, between __ and between __

• Spongiform: Small __

• Encephalopathy: __ dysfunction

PrPSc, PrPc, post-transcriptional, exponentially, aggregate, neuronal

Proposed Conversion Mechanism of prion proteins

1. __ proteins enter cell

2. PrPSc interacts with __ proteins

3. __-__ folding modifications occur to form another abnormally folded prion protein

4. Abnormal conversion continues __ with other normal prion proteins

5. PrPSc prion proteins __ in neurons or immune cells

6. __ death leading to specific pathology

Aggregation, neuronal, prion, gliosis, vacuoles

Pathogenesis of TSEs

• Protease-resistant prion __

• __ death and thus __ release

• __ leads to scaring

• Spongiform appearance from __

Gliosis, scaring, all

__ is a neuro-immune injury response developing __ (pathology) of the brain

• common in __ (some/all) TSEs

Local, peripheral, BBB, macrophages, reactive phenotype

TSEs induce limited __ (local/systemic) immune response

• No __ immunity generated

• The __ protects against damaging inflammation

• Microglia serve as brain’s __ that phagocytose PrPSc

• Astrocytes are neuroprotective cells with __ __

PrP, misfolding, brain, phenotypes

Misfolded PrPSc variants

• Distinct __ mutations

• Distinct protein __ (i.e. Beta sheet)

• Differential __ accumulation

• Distinct disease __

Secretions, Bovine Spongiform Encephalopathy, vCJD

Acquired prion transmission from animals

• Excreted in animal body __

• Acquired Transmission from __ __ __ from cows, but no evidence of human disease from chronic wasting disease or scrapie

  • Leads to __

Sporadic, 129 MV, 129 VV

Creutzfeldt-Jakob Disease (CJD)

• 85% __ origin, mutation (sCJD)

• PrPSc - __ __ or __ __ (met/val) increases susceptibility to beta-sheet transformation

Genetic, E200K

Creutzfeldt-Jakob Disease (CJD)

• 15% __ origin, mutation (gCJD)

• PrPSc - __ (glutamine → lysine) increases susceptibility to beta-sheet transformation

60-70, cerebral cortex

Creutzfeldt-Jakob Disease (CJD)

• Disease onset - __-__ years old

• Disease course - 6 months impacting the __ __

CJD sx

Depression, numbness/tingling, reduced coordination + cognition, immobility, lack of responsiveness, 100% fatality - death

129 MM, 20-30

Acquired Variant Creutzfeldt-Jakob Disease (vCJD)

• Acquired PrPSc - __ __ (methionine homozygote) is a susceptibility factor

• Rare - disease onset at __-__ years old

vCJD sx

CJD symptoms and dysesthesias (itching/burning/pain at touch)

Acquired Iatrogenic Creutzfeldt-Jakob Disease (iCJD)

PrPSc transmission from infected bodily fluids, tissues, or contaminated medical supplies

Dura mater/corneas, hormone, PrPc

• Other forms of iCJD transmission

  • Organ transplants of infected __ __ and __ (tissues)

  • Infected __ preparations

  • Infects cells expressing __

D178N, thalamic hypo, 13-60

Fatal Familial Insomnia (FFI)

• PrPSc - ___ (aspartic acid to asparagine) increases susceptibility to beta-sheet transformation

• Inherited, sporadic or acquired mutation

• Increasing __ __metabolism

• Disease onset: __-__ years old

FFI Stage I, hallucinations

__ __ __ notes progressive insomnia, phobias, anxiety

FFI Stage II - Psychiatric issues worsen with added __

FFI Stage III, dementia, coma, death

__ __ __ notes complete insomnia and weight loss

FFI Stage IV - __, __, then __

Genetic, 40-50, P102L, 5

Gerstmann-Straussler-Scheinker Syndrome (GSS)

• Primarily __ mutation increases susceptibility to beta-sheet transformation

• Disease onset ranges from ages _-__

• PrPSc - __ (proline to leucine)

• Disease course of _ years average

GSS sx

Cerebellar ataxia, abnormal eye movement, optic atrophy, paralysis, death

Symptom, onset, histology, EEG, MRI, CSF

General Dx of TSEs

• __ology, age of __

• __ is huge indicator, also __ studies and __ imaging

• Increased __ proteins

Shaking, conversion, PrPSc, fluorescence, sensitivity

Real-Time Quacking Induced Conversion (RT-QulC)

• (1) __ to fragment prion aggregates

• (2) Cycles of fragmentation and __ of PrPc to PrPSc

• (3) Visualization of__ aggregates with __

• Extremely high __ and specificity

Spongiform, cerebral cortex

For CJD histology

• Observing __ degeneration

• At the ___

PrPSc, multicentric, cerebellum

For GSS histology

• Observing __ plaques, specifically __ plaques

• At the __

Gliosis, thalamus, brainstem

For Familial insomnia histology

• Observing __ only, common in all TSEs

• At the __ and __

Daisy, amyloid, vacuoles, cerebral cortex

For vCJD histology

• Observing florid plaques

• “__” arrangement of __ deposits surrounded by __

• At the ___

Decontamination, donations, livestock

Prevention of TSEs

• Family planning with familial cases

• __ is critical to prevent iCJD

• If dx, do not offer organ __

• Newer regulations for handling/feeding __

Fatal, hospice care

Current therapeutics for TSEs

• None as diseases are always __

• __ __ is advised for supporting neuropsychiatric decline